Rev Endocr Metab Disord (2016) 17:389–403
DOI 10.1007/s11154-016-9393-9
Obesity as a risk factor for malignant melanoma
and non-melanoma skin cancer
K. Karimi 1 & T. H. Lindgren 1 & C. A. Koch 2,3,4 & Robert T. Brodell 5,6,7
Published online: 10 November 2016
# Springer Science+Business Media New York 2016
Abstract The dramatic increases in incidence of both obesity
and many cancers including skin cancer emphasize the need to
better understand the pathophysiology of both conditions and
their connections. Melanoma is considered the fastest growing
cancer and rates of non-melanoma skin cancer have also in-
creased over the last decade. The molecular mechanisms un-
derlying the association between obesity and skin cancer are
not clearly understood but emerging evidence points to chang-
es in the tumor microenvironment including aberrant cell sig-
naling and genomic instability in the chronic inflammatory
state many obese individuals experience. This article reviews
the literature linking obesity to melanoma and non-melanoma
skin cancer.
Keywords Melanoma . Obesity . Non-melanoma skin
cancer . Basal cell carcinoma . Squamous cell carcinoma .
Inflammation . Leptin . Insulin
* Robert T. Brodell
rbrodell@umc.edu
1
School of Medicine, Texas Tech University Health Sciences Center,
Lubbock, TX, USA
2
Division of Endocrinology, University of Mississippi Medical
Center, Jackson, MS, USA
3
Cancer Institute, University of Mississippi Medical Center,
Jackson, MS, USA
4
G.V. (Sonny) Montgomery VA Medical Center, Jackson, MS, USA
5
Department of Dermatology, University of Mississippi Medical
Center, 2500 North State Street, Jackson, MS 39216, USA
6
Department of Pathology, University of Mississippi Medical Center,
Jackson, MS, USA
7
Department of Dermatology, University of Rochester School of
Medicine and Dentistry, Rochester, NY, USA
1 Introduction
Obesity is a leading cause of chronic illness and morbidity.
It contributes heavily to both individual and societal health
expenditures, and accounts for nearly 20 % of all cancer cases
[1]. A variety of factors are at play in the progression of cancer
in patients with obesity and/or type 2 diabetes [2]. Increased
weight or height directly correlates with the number of total
cells available for malignant transformation [3]. In addition,
cancer may be caused by obesity-induced modifications of the
immune system or long-term storage of toxins or medications
in adipose tissue [4, 5]. Whether obesity increases the risk of
melanoma or non-melanoma skin cancers (NMSC) is less well
established.
Several studies have demonstrated a link between malig-
nant melanoma and excess adiposity [6–11], although a large
study demonstrated no association [12, 13]. Other studies sug-
gested obesity is associated with an increased risk of malig-
nant melanoma in males [14–16] but not females [13, 14,
16–20]. Similarly, there is conflicting evidence with regard
to obesity and NMSC. In one study, excess body weight and
body mass index (BMI) were inversely associated with the
development of NMSC [12, 13], while a positive association
between obesity and NMSC has also been described [21, 22].
Courneya and colleagues proposed that obesity may be a sig-
nificant risk factor for the development of skin cancer only in
areas with lower UV radiation. The impact of higher UV ra-
diation inducing NMSC may overshadow the less significant
effects of obesity [21].
2 Obesity
Obesity rates have dramatically increased in the USA over the
past three decades, doubling in the last 25 years [23, 24].
390
According to the US Centers for Disease Control and
Prevention (CDC), 35 % of the US population is obese, and
6 % of the population is extremely obese (Obesity Prevalence
Maps, Centers for Disease Control and Prevention
http://www.cdc.gov/obesity/data/prevalence-maps.html).
The 13th annual report from Trust for America’s Health
and the Robert Wood Johnson Foundation found that rates
of obesity now exceed 35 % in four states, are at or above
30 % in 25 states, and are above 20 % in all states
(http://healthyamericans.org/reports/stateofobesity2016).
Even more troubling, the prevalence of obesity has tripled in
children and adolescents over the past 40 years. Obesity
prevalence is also increasing in both developed and
developing nations [25, 26].
The cause of obesity is not clear, but interactions between
environmental factors (e.g., gut microbiota, ambient tempera-
ture, energy balance, excessive caloric intake, and insufficient
physical activity) and genetic factors, some reflected by pig-
mentation [27–31], play a role. The genes that regulate tan-
ning ability and pigmentation of hair, skin, and eyes may be
associated with intrinsic factors that produce obesity [32, 33].
Infections may also contribute to obesity [34]. Adipocytes and
macrophages are similar [35], and pre-adipocytes have the
ability to rapidly and efficiently differentiate into macro-
phages, thereby linking fat and innate immune processes
[35]. Furthermore, adipose tissue may expand in response to
infection [34].
2.1 Obesity and inflammation
Inflammation may be associated with obesity, reflecting
the body’s response to pro-inflammatory cytokines [34,
36]. Pro-inflammatory markers like macrophage colony-
stimulating factor (MCSF) can predict obesity in human
subjects [37, 38]. In both diet-induced and genetic obesity
[39], adipose tissue becomes infiltrated with adipose tis-
sue macrophages (ATM). These ATMs produce pro-
inflammatory cytokines including interleukin 8 (IL-8),
monocyte chemo-attractant protein-1 (MCP-1), tumor ne-
crosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and
complement proteins [40–42]. Leukocytes are also in-
creased [43], reflecting low-grade systemic inflammation.
Inflammatory kinases further amplify inflammation in
obese individuals [44].
In addition to promoting obesity-induced angiogenesis, in-
flammation may also promote tumorigenesis and melanoma
growth [45]. Adipocytes secrete inflammatory cytokines that
recruit macrophages to initiate angiogenesis [24].
Macrophages may play a central role in both angiogenesis of
melanoma and of obesity via upregulation of the vascular
endothelial growth factor (VEGF) pathway accelerated by
leptin [24].
Rev Endocr Metab Disord (2016) 17:389–403
2.2 Obesity and oxidative stress
Systemic oxidative stress is another characteristic of obesity
[46]. Obese subjects exhibit reductions in antioxidant capaci-
ty, elevated reactive oxygen species (ROS) production, and
increased serum lipid oxidation products [47–49]. Adipose
tissue itself appears to be the major source of systemic oxida-
tive stress in obesity [50]. Additionally, as expansion of adi-
pocytes occurs, the distance between adipocytes and capil-
laries increases, leading to adipose tissue hypoxia [46]. In
mice, adipose tissue hypoxia has been shown to further pro-
mote systemic oxidative stress by suppression of glutathione
peroxidase 3 (GPx3), leading to exacerbation of glucose-
induced insulin resistance [46].
2.2.1 Diet and obesity
High-fat, high-carbohydrate, and high-caloric diets contribute
to obesity. Cancer can also be influenced by diet. Excessive
meat consumption (i.e., greater than 5 servings per day), in
particular, is associated with greater incidence of cancer be-
cause of environmental carcinogens present in meat and char-
cuterie products [51]. Specifically, cooked fish and beef con-
tain heterocyclic amines called aminoimidazole-arenes
(AIAs) that are pro-mutagens and pro-carcinogens [52].
While these factors are present in low levels in these foods,
excessive consumption may induce carcinogenic effects in
obese individuals.
2.2.2 Genetics and obesity
Ethnicity and specific gene pathways contribute to the
development of obesity. Several causal single nucleotide
polymorphisms (SNPs), including those in or near the
mitochondrial carrier 2 (MTCH2) and melanocortin 4
receptor (MC4R) genes, are associated with obesity.
These SNPs are more significant in Caucasian and
Hispanic subjects compared to Chinese and African
American people [53]. Furthermore, total cholesterol,
which is directly related to obesity, is higher in Black
children, who are also significantly more likely to be
obese than White or Asian children [54].
The rapamycin (MTOR) pathway may link obesity and
cancer mechanisms. As a regulator of cell growth, prolifera-
tion, and survival, the MTOR gene is activated by oxidative
stress, which is increased in obese individuals [55]. Under
stress, the mTOR gene promotes cell survival and proliferation
as well as gene transcription to metabolize carbohydrates, in-
crease lipogenesis, and inhibit autophagy [55]. Thus, MTOR
allows for the proliferation and survival of cancer cells and
promotes metastases.
Rev Endocr Metab Disord (2016) 17:389–403
2.3 Obesity and the immune system
Adipose tissue inflammation is a risk factor for developing and
advancing breast cancer because of adipose tissue’s tendency to
sequester the proangiogenic factor MCP-1 [56]. MCP-1 is a
chemokine that regulates the migration of monocytes and mac-
rophages and is involved in cancer pathology. Diet-induced
obese mice were also found to have variable carcinogenesis-
related gene expression: cellular proliferation, antioxidant and
DNA protection, and tumor suppression genes [57].
ROS are important in cellular communication and homeo-
stasis; however, an inappropriate increase in ROS in the body
can contribute to chronic diseases like type 2 diabetes and
cancer [58]. Oxidative stress can induce carcinogenesis as
well as reduce the effects of anti-oxidants [59, 60]. In an an-
imal study, researchers discovered that obese mice were more
likely to exhibit immune system deterioration [61]. This pre-
mature immunosenescence suggests a link between obesity
and an impaired immune system. Interestingly, inflammation
responses in the body also produce the same exogenous oxi-
dative stress in melanocytes that elicits generation of ROS in
melanocytes [62]. Therefore, a link between obesity-
associated inflammation and ROS accumulation contributing
to melanoma pathogenesis can be suggested.
The obese mutation in the leptin gene can also contribute to
obesity. Leptin, a hormone that regulates appetite, is reduced
in people with obesity [44, 63] and is positively associated
with melanoma risk [64]. Leptin mediates macrophage re-
sponse to ROS intracellularly [65] and induces oxidative
stress via TNF-alpha [66]. Decreased leptin or leptin resis-
tance results in an impaired ability to maintain immunity in
people with obesity. Interestingly, leptin is also a reliable tu-
mor marker of malignant melanoma, as its expression is sig-
nificantly increased in human melanoma cells [67]. The inter-
play between these factors suggests obesity as an important
risk factor for melanoma.
2.4 Obesity and vitamin D
Vitamin D has a positive, pro-inflammatory role in white ad-
ipose tissue [68], and obese people often have an accompany-
ing vitamin D deficiency [69]. This deficiency may be respon-
sible for 20 % of obesity-related cancer risk [70]. However,
the causal relationship between vitamin D deficiency and obe-
sity has yet to be determined (i.e., whether vitamin D is a
consequence of obesity or a risk factor for increased adiposi-
ty). People with obesity may consume fewer foods that con-
tain vitamin D or avoid exposed to the sun due to a sedentary
lifestyle. Vitamin D may also lower leptin concentrations,
impacting appetite [69]. Finally, adipose tissue traps vitamin
D, lowering serum vitamin D concentrations [71]. Both vita-
min D deficiencies [72] and obesity [73] have been associated
with a higher risk of cancer.
391
2.5 Obesity and insulin
Inflammatory cytokines from adipose tissue produce chronic
inflammation that can induce insulin resistance and type 2
diabetes mellitus [74, 75]. This results in increased pancreatic
insulin secretion to compensate for the cells’ lack of insulin
uptake. Hyperinsulinemia then can induce tumorigenesis [2].
Cancer cells react with highly concentrated insulin in the
ex trace llular-sign al-re gula te d k inase (ERK) a nd
phosphatidylinositol-3 kinase (PI-3K) pathways [76].
Malignant cancer cells also overexpress insulin receptors, pro-
moting insulin-induced cell proliferation [76].
Hyperinsulinemia in obese individuals and type 2 diabetics
has been associated with acanthosis nigricans, acrochordons,
finger pebbles, and Leser-Trelat, highlighting the link between
insulin level and cell proliferation [77].
Adiponectin, an adipokine that opposes insulin resistance,
is significantly decreased in obese individuals, increasing can-
cer risk [76].
Insulin-like growth factor-1 is elevated in patients with
acromegaly which is caused by growth hormone excess and
can lead to secondary diabetes mellitus [78]. Acromegalics
with diabetes mellitus are three times more likely to develop
malignant tumors [79].
2.6 Obesity and hypoxemia
Hypoxemia is a commonly underappreciated feature of obe-
sity that results from over perfusion of poorly ventilated lung
regions [46]. In many obese patients, closing volume exceeds
functional residual capacity (FRC), and tidal breath is initiated
from volumes at which many airways in the inferior parts of
the lung are closed [46]. Hypoxia enhances systemic inflam-
mation, impacting all organ systems [46]. Chronic hypox-
emia, in turn, increases plasma leptin levels [80].
3 Melanoma
Melanoma is the most aggressive form of skin cancer (Fig. 1),
and it most commonly develops from malignant transforma-
tion of melanocytes at the epidermal-dermal junction [81].
The incidence of malignant melanoma has been increasing
consistently since the 1950s [82–85]. Over a 10-year period,
melanoma incidence rates doubled in all socioeconomic
groups [86]. While patients with a higher SES are more likely
to be diagnosed with melanoma, individuals with a lower SES
or those without health insurance are more likely to have ad-
vanced stage melanoma at diagnosis and are more likely to die
from melanoma [86–89]. While sun exposure behaviors are a
major factor affecting the melanoma epidemic [90], part of the
recorded increase may be the result of expansions in screen-
ing, biopsy, and reporting to cancer registries [91–94].
392 Rev Endocr Metab Disord (2016) 17:389–403

Table 2 Other possible risk factors for the development of malignant

melanoma

Cosmetics [110]
Lightening agent:
Rhododendrol [110]
Preservatives [111]:
Parabens [112]
Estrogenic molecules [113]
Environmental exposures
Heavy metals (Cu, Fe, Mn, and Co) [114–118]
Non-metals in pesticides, herbicides, dyes, organic
amines, and polychlorinated phenyls [114–118]
Obesity and increased serum leptin levels [64]

pigmentation; this suggests several possible links to obe-

Fig. 1 This 3 × 3 cm black lesion shows asymmetry, irregular borders,
variegation of color (tan and black) has been enlarging over several years.
A brown, waxy stuck-on seborrheic keratosis is present nearby
3.1 Risk factors
The well-accepted risk factors for melanoma are detailed in
Table 1. Less well-accepted risk factors including obesity are
highlighted in Table 2.
4 Mechanisms for the association of melanoma
and obesity
4.1 Melanocortin system and the POMC gene
Melanocortins play a role in energy homeostasis, steroido-
g en es i s, i nf l am mat i on , i m m un om od ula tio n , an d
Table 1 Well-known risk factors for the development of malignant
melanoma
Greater than 25 nevi [95]
Fair eye color (blue, green, and hazel) [96]
Light hair color (red > blond > light brown) [96]
Family history melanoma [96]
Personal or family history of non-melanoma skin cancera [97]
Host genome [98]
Childhood cancer [99]
Ultraviolet related
Intermittent sun exposure and sun burn [100]
Living in lower latitudes [100]
Living at higher altitude [101–103]
Indoor tanning [104]
Alcohol consumption [105–109]
a
This association could be the result of detection bias [98]
sity [119]. In fact, a genetic link between obesity and
pigmentation [120–124] has been suggested by linking
early-onset obesity with red hair color in patients with
pro-opiomelanocortin (POMC) mutations [119, 125].
Features of POMC gene mutations include severe obesity,
phototype I skin, and red hair [126, 127]. POMC gene
transcriptional activation follows DNA damage induced
by UV radiation in epidermal melanocytes [128, 129].
Furthermore, increased expression of corticotropin-
releasing hormone, which may stimulate POMC expres-
sion, may serve as a melanoma growth factor, as there is
evidence that it is present in pigmented lesions [130]. A
variety of POMC peptides are made by different cell
types. Thus, the prohormone gene exhibits a wide range
of control over multiple physiologic functions [119]
(Fig. 2).
MSH and ACTH, post-translational products of the
POMC prohormone, are produced locally in the skin and
bind to melanocortin 1 receptor (MC1R) on melanocytes
to increase melanin production [119]; a POMC deficiency
results in fair skin and red hair [126] and an increased risk
for both malignant melanoma and NMSC [126].
Additionally, MSH binds to feeding centers like
melanocortin 4 receptor (MC4R) to decrease feeding
[127, 131]; therefore, POMC deficiency also results in
obesity. This suggests that melanoma and obesity are not
directly related, but rather that a third instigate, POMC
deficiency, links their development.
POMC neurons are the target of circulating leptin, further
suggesting that body weight and skin pigmentation are cru-
cially linked [131]. Alterations in the leptin pathway may
correlate with a cutaneous carcinogenic cytokine response to
UV radiation [132].
Cutaneous melanomas can be divided into the subtypes
NF1, RAS (N/H/K), BRAF, and Triple-WT (lack of hot spot
mutations in NF1, RAS (N/H/K), BRAF) with immune infiltra-
tion being associated with improved survival [133].
Rev Endocr Metab Disord (2016) 17:389–403
Lepn
LEPRb
LEPRb
AgRP
POMC neurons
neurons
Neuropepde Y
POMC
Appete
ACTH α-MSH
MC1R MC3R * MC4R *
Melanin Appete
* Deleon of these receptors results in Lepn Resistance and obesity
Fig. 2 Leptin and POMC and AgRP neuron interactions
4.2 Increased leptin
Obesity-associated cancers demonstrate increased leptin
levels [134–137] because of leptin resistance in many obese
people. Leptin levels are positively correlated with BMI, total
abdominal fat volume, and subcutaneous fat volume [138]. In
fact, one of the major factors influencing plasma leptin con-
centrations is adipose tissue mass [134]. Adipocyte synthesis
of leptin is influenced by several factors, including insulin
[139], TNF-alpha [140], glucocorticoids [141], gonadal hor-
mones [142], catecholamines, and prostaglandins [143]. Some
of these factors have been associated with neoplastic process-
es (Fig. 3).
Leptin also promotes cell division, proliferation, and pos-
sible melanoma metastasis [64, 144]. High fat diet may further
promote melanoma progression [145]. High serum leptin is
positively correlated with melanoma risk [64] by accelerating
melanoma tumor growth [24]. Furthermore, leptin antagonist
antibodies have been found to decrease melanoma progres-
sion [146]. The correlation between serum leptin levels and
melanoma risk requires further study to determine if leptin
plays a significant role in the development of melanoma.
4.2.1 Role of leptin in obesity
Leptin inhibits insulin secretion and lipogenesis [147, 148],
stimulates lipolysis and fatty acid oxidation [149, 150], sup-
presses appetite, and promotes energy expenditure, ultimately
393
decreasing body weight [149, 151–154]. Leptin resistance can
result from defects in leptin transport [155–157], impaired
LEPRb signaling [158, 159], neuronal energy imbalance
[149], or endoplasmic reticulum (ER) stress. Leptin deficiency
and leptin resistance are risk factors for obesity [149,
160–162] and are associated with insulin resistance [163,
164] and hypogonadism [161, 165, 166].
Leptin activates leptin receptor long isoform (LEPRb) in the
hypothalamus, acting on both POMC neurons and agouti-
related protein (AgRP) neurons [149]. This results in increased
activation of melanocortin 3 (MC3R) and MC4R to suppress
appetite [162, 167] and inhibit feeding behaviors [149, 168].
Leptin resistance promotes ER stress and chronic inflam-
mation that contribute to insulin resistance [169–171].
Notably, ER stress inhibits leptin signaling [172, 173].
4.2.2 Role of leptin in melanoma
Increased circulating leptin results in metabolic disturbances,
that are compounded by inflammation [163, 174]. Leptin is
structurally similar to pro-inflammatory cytokines and may
modulate CRP [174, 175]. It is therefore plausible that the
positive associations found between serum leptin levels and
skin cancer may be due to inflammation secondary to leptin
resistance and obesity (Fig. 4).
Leptin may also be a cause of melanoma growth via in-
creased nitric oxide (NO) production and increased levels of
circulating endothelial progenitor cells (EPCs), ultimately pro-
moting angiogenesis [176] and vasculogenesis [177] mediated
by VEGF and endogenous fibroblast growth factor 2 (FGF-2)
[178, 179].
Leptin acts as a pro-inflammatory adipokine that influences
cytokine production, cellular immunity, and inflammation
[180]. Additionally, leptin decreases the expression of the tu-
mor suppressor p53 [181] to promote cell cycle progression.
Furthermore, melanoma cells, but not melanocytes, express
the leptin protein, ultimately creating a positive autocrine
feedback loop [81] that contributes to uncontrolled prolifera-
tion of melanoma tumor cells.
Epidermal hypoxia reduces apoptosis and favors survival
of melanoma cells [182]. Hypoxic conditions also increase
leptin levels via hypoxia-inducible factor 1-alpha (HIF-1-al-
pha) [183]. In addition to stimulation by hypoxia, HIF-1-alpha
is also activated by insulin, insulin-like growth factor (IGF),
angiotensin II, thrombin, platelet-derived growth factor
(PDGF), endothelin-1, interleukins, and TNF-alpha [183].
4.3 Other connections between obesity and melanoma
4.3.1 Decreased adiponectin
Adiponectin has anti-tumor effects by inhibiting cell prolifer-
ation [184–189]. Adiponectin levels are approximately 50 %
394 Rev Endocr Metab Disord (2016) 17:389–403

Fig. 3 Regulatory pathways of Insulin Glucocorcoids

leptin TNF-α
Gonadal Prostaglandins
hormones Catecholamines

Adipocyte
Lipolysis
Energy B-Oxidaon
Body Obese
Expenditure gene
Weight Pancreac B Insulin
Cells
Vitamin D
Lepn

Serum Macrophages ROS

FGF2 Nitric Oxide
VEGF EPCs
Hypothalamus Cytokines
Angiogenesis &
Vasculogenesis Skin

Appete Inflammaon
Proliferaon
Melanin
Tumor Growth Weight Gain Obesity

Lepn
Anbodies Melanoma

lower in obese individuals [189]; this allows for increased cell
proliferation. Mantzoros and colleagues, however, found that
the inverse relationship between serum adiponectin and mel-
anoma is not significant [190].
4.3.2 Insulin resistance and insulin-like growth factor
Increased insulin, IGF-1, and IGF-2 are sufficient to induce
tumorigenesis via the insulin receptor [191]. Inflammatory
kinases inhibit insulin action and glucose uptake [44] in obese
individuals. Hyperinsulinemia and increased levels of IGF-1
may contribute to an increased cancer risk and cancer progres-
sion; on the other hand, calorie restriction, intentional weight
loss, and diabetes treatments may reduce the risk and rate of
skin cancer progression [2, 192]. The IGF-1 receptor, in par-
ticular, inhibits cell proliferation, differentiation, and survival
in the skin, and its inactivation results in abnormal differenti-
ation patterns in keratinocytes [193].
Another pathway involved in insulin resistance is the phos-
phatidylinositol 3-kinase/protein kinase B (PI3K/Akt) path-
way in which a PI3K inhibitor and an MTOR inhibitor result
in the proliferation and prolonged survival of melanoma cells

Genec UV Radiaon Neuronal energy imbalance

Factors Impaired LEPRb signaling
Lepn Transport Defects
Genec Factors

HIF-α
Lepn Deleon of
Deficiency MC3R or MC4R
Fat
Insulin
Dysregulaon or
Resistance Lepn Increased Circulatory P53 Phosphorylaon of Rb
Lipodystrophy
Resistance Lepn

Obesity Nitric Oxide Apoptosis

ER Stress EPCs E2F
Chronic Inflammaon +
Feedback Angiogenesis &
Loop
Vasculogenesis
Hypertension

Melanoma
Diurec Use Cells

BCC
Proliferaon

Tumor Growth
Fig. 4 Potential interactions between leptin, basal cell cancer, and melanoma cells
Rev Endocr Metab Disord (2016) 17:389–403
[194]. The activation of this pathway also mediates melanoma
cell resistance to chemotherapeutic drugs.
Inappropriately increased insulin and IGF are associated
with inflammation, decreased physical activity, and an im-
paired immune system [76]. IGF-1, in particular, associates
with VEGF to induce neovascularization and metastases
[76]. Furthermore, IGF-2 is associated with tumorigenesis
via the insulin and IGF receptors [76].
Serum levels of IGF-1 are significantly increased in pa-
tients with melanoma [195] in which lowered insulin-like-
factor-binding-proteins 3 and 5 (IGFBP-3 and IGFBP-5)
levels are associated with melanoma cell proliferation, metas-
tases, and reduced survival rates [36, 196].
4.3.3 Glucocorticoids
Glucocorticoids are the most common treatment for inflam-
matory disorders including those of the skin; however, they
also have significant negative effects on metabolism [197]. In
recurrent malignant melanoma patients, the glucocorticoid re-
ceptor is overexpressed on melanoma cells [198].
Glucocorticoids have been shown to significantly reduce tu-
mor size and improve outcomes because they induce apopto-
sis in melanoma cells [199].
In obese individuals, glucocorticoids and psychological
stress also have an impact on appetite regulation and metabo-
lism [200]. Obese individuals tend to have overactive 5-alpha-
reductase, which inactivates cortisol and, therefore, affects
glucocorticoid metabolism [201].
4.3.4 FTO gene SNPs
More recently, it has been discovered that peroxisome
proliferator-activated receptor gamma (PPARG) co-activators,
which are key regulators of energy metabolism, also regulate
the production of melanin in response to alpha-MSH in mela-
nocytes. PPARG co-activators are also associated with tan-
ning, providing a novel link between pigment formation and
energy metabolism [202].
The fat mass and obesity-associated protein (FTO) gene is
important in pigmentation and melanoma development [27].
While obesity-related SNPs are independent of both pigmen-
tary and melanoma-related FTO gene variants, it is likely that
the FTO gene influences multiple phenotypes. Common var-
iability in the FTO gene is associated with increased obesity
[203], and the FTO gene may also be important in pigmenta-
tion and melanoma development [27].
4.3.5 Diet
There are a variety of chemicals and environmental factors in
food that contribute to the development of and rise in obesity
worldwide. One particular group of chemicals linked to
395
obesity are endocrine distributing chemicals like
polychlorinated biphenyls [204], which are also associated
with the development of various cancers [205]. Many addi-
tives and preservatives like pesticides, herbicides, dyes, organ-
ic amines, and polychlorinated phenyls bind melanin [62,
114–118]. This increases the pro-oxidant response of melanin,
resulting in a build-up of ROS, which is a prominent feature
during melanoma pathogenesis [62]. Thus, quality of food
ingested can contribute to obesity as well as constitutive oxi-
dative stress and melanoma [206].
4.3.6 Medications
Some medications are associated with both obesity and pho-
tosensitization. Obesity also reduces the rate of drug metabo-
lism, increasing the intensity and duration of photosensitiza-
tion [207], which could contribute to melanoma development.
Diuretics are the first line of treatment for individuals with
hypertension [208], and obesity and increased leptin levels
facilitate hypertension. Overweight and obese individuals
using diuretics have an increased risk of BCC [209–212] be-
cause diuretics increase the risk of phototoxicity and
photocarcinogenesis [213–215].
Obese individuals, because of chronic systemic inflamma-
tion, may also take medications like nonsteroidal anti-
inflammatory drugs (NSAIDs), which are also associated with
heightened photosensitivity [216, 217]. These cutaneous reac-
tions could be due to the drugs’ effects on the immune system
via inflammatory pathways.
BComfort eating^ is associated with psychological stress
and depressive symptoms [218], and psychiatric or mood-
stabilizing medications are known to increase patients’ sus-
ceptibility to UV damage [219–221]. Sugar and sweet taste
may have analgesic effects. Amazingly, an American child
after age 2 years on any given day is more likely to consume
a sugar-sweetened product than a fruit or vegetable [222].
Fig. 5 Basal cell cancer. This 16 × 10 mm ulcerated, crusted plaque with
a pearly border is noted on the left bridge of the nose in an elderly patient
with sun-damaged skin
396 Rev Endocr Metab Disord (2016) 17:389–403

Table 4 Other possible risk factors for the development of non-

melanoma skin cancer

Diuretics or other photosensitizing medications [209–212]

Alcohol consumption [233]
High-fat diet [228]
Smoking [235]

Other risk factors of NMSC are noted in Table 3. Less well-

accepted risk factors are highlighted in Table 4. Obesity is best
characterized in this second group.
Fig. 6 Squamous cell cancer. A 6 × 6 cm eroded, crusted ulceration with In addition to the photosensitizing and mutagenic ef-
focal verrucous changes is noted on the right cheek and a 3 × 4 cm moist fects of acetaldehyde, alcohol consumption may promote
erythematous ulceration is noted on the right ear in this elderly patient skin cancer through impairment of the immune system
with a long history of sun exposure
compounded by poor nutritional status [236, 237]. In
fact, people who drink over 10 g/day of alcohol are 1.8
5 Non-melanoma skin cancers (NMSC)
times more likely to develop skin cancer than those who
do not drink alcohol [236, 237]. Alcohol consumption
Basal cell cancer (Fig. 5) originates from stem cells in the
may also be a marker for health risk behaviors like ex-
hair follicle infundibulum or interfollicular epidermis and
cess sun exposure [105–109]. Finally, cigarette smoke,
accounts for 90 % of all skin cancers [223]. It is primarily
which contains chemicals like arsenic, may be associated
driven by the sonic hedgehog pathway [224]. In the USA,
with cancers including SCC and BCC [235, 238–241].
approximately 1 million new cases of BCC are diagnosed
Long-term exposure to high levels of inorganic arsenic,
each year [225]. This rapid increase is likely due to life-
which occurs naturally but is also found due to pesticide and
style factors and levels of UVA radiation. Skin aging,
fertilizer use, is associated with higher rates of skin, bladder,
which primarily affects the basal cell layer of skin, is
and lung cancers, as well as heart disease. The FDA is currently
caused by both genetic and environmental factors and
examining these and other long-term effects and has set the
contributes to changes in DNA repair and stability, cell
maximum level of inorganic arsenic in infant rice cereal at
cycle and apoptosis, and cellular metabolism; aging may
1 0 0 - p a r t s - p e r - b i l l i o n ( h t t p : / / w w w. f d a .
also alter hormones that regulate tumor suppressor path-
gov/Food/FoodborneIllnessContaminants/Metals/ucm280202.
ways to influence carcinogenesis [226]. Squamous cell
htm).
carcinoma (Fig. 6) arises from the cells of the spinous
Factors that decrease the risk of developing NMSC are
layer of the epidermis. The incidence of squamous cell
detailed in Table 5.
carcinoma (SCC) has also drastically increased over the
past several decades [227]. A high-fat diet may contribute
to the development of SCC due to higher phospholipid
and cholesterol content in cancerous and pre-cancerous
6 Conclusion
skin lesions [228]. On the other hand, stromal adipocytes
may promote the differentiation of squamous cell carcino-
The dramatic increases in incidence of both obesity and skin
ma cells and inhibit their growth [229].
cancer emphasize the need to better understand the pathophys-
iology of both conditions and their connections. Melanoma is
considered the fastest growing cancer and non-melanoma skin
Table 3 Well-known risk factors for the development of non- cancer is also on the rise. The majority of the literature sug-
melanoma skin cancer
gests an association between obesity and both melanoma and
Ultraviolet radiation [12, 225, 230] NMSC. With several points of convergence, further research
Closer proximity to equator [231]
Age [232, 233] Table 5 Well-known factors that decrease risk for the development of
non-melanoma skin cancer
Fair eye color (blue, green, and hazel) [209]
Light hair color (red > blond > light brown) [209] Excess body weight [12, 13]
Fair complexion [209] Less baseline sun exposure [12, 13, 19, 242]
Immunosuppression [234] Less physical activity outdoors [12, 13, 19, 242]
Genetic influences [234] Less revealing clothing [233]
Rev Endocr Metab Disord (2016) 17:389–403
is necessary to explore and dissect the intricate relationships
between obesity and skin cancer.
Compliance with ethical standards
Conflict of interest The authors Karen Karimi, Robert Brodell, Taylor
Lindgren, and Christian A. Koch declare that there is no relevant conflict
related to this work.
References
1. Wolin KY, Carson K, Colditz GA. Obesity and cancer. Oncologist.
2010;15(6):556–65. doi:10.1634/theoncologist.2009-0285.
2. Gallagher E, LeRoith D. Obesity and diabetes: the increased risk
of cancer and cancer-related mortality. Physiol Rev. 2015;95(3):
727–48.
3. Albanes D, Winick M. Are cell number and cell proliferation risk
factors for cancer? J Natl Cancer Inst. 1988;80(10):772–4.
4. Scrimshaw NS, SanGiovanni JP. Synergism of nutrition, infection,
and immunity: an overview. Am J Clin Nutr. 1997;66(2):464S–
77S.
5. Koch CA, Diamanti-Kandarakis E. Introduction to endocrine
disrupting chemicals—is it time to act? Rev Endocr Metab
Disord. 2015;16(4):269–70.
6. Kirkpatrick CS, White E, Lee JA. Case–control study of malig-
nant melanoma in Washington State. II. Diet, alcohol, and obesity.
Am J Epidemiol. 1994;139(9):869–80.
7. Samanic C, Chow WH, Gridley G, Jarvholm B, Fraumeni Jr JF.
Relation of body mass index to cancer risk in 362,552 Swedish
men. Cancer Causes Control. 2006;17(7):901–9. doi:10.1007
/s10552-006-0023-9.
8. Samanic C, Gridley G, Chow WH, Lubin J, Hoover RN,
Fraumeni Jr JF. Obesity and cancer risk among White and Black
United States veterans. Cancer Causes Control. 2004;15(1):35–
43. doi:10.1023/B:CACO.0000016573.79453.ba.
9. Dubin N, Moseson M, Pasternack BS. Epidemiology of malignant
melanoma: pigmentary traits, ultraviolet radiation, and the identi-
fication of high-risk populations. Recent Results Cancer Res.
1986;102:56–75.
10. Gallus S, Naldi L, Martin L, Martinelli M, La Vecchia C.
Oncology Study Group of the Italian Group for Epidemiologic
Research in D. Anthropometric measures and risk of cutaneous
malignant melanoma: a case–control study from Italy. Melanoma
Res. 2006;16(1):83–7. doi:10.1097/01.
cmr.0000194429.77643.76.
11. Dennis LK, Lowe JB, Lynch CF, Alavanja MC. Cutaneous mela-
noma and obesity in the Agricultural Health Study. Ann
Epidemiol. 2008;18(3):214–21. doi:10.1016/j.
annepidem.2007.09.003.
12. Tang JY, Henderson MT, Hernandez-Boussard T, Kubo J, Desai
M, Sims ST, et al. Lower skin cancer risk in women with higher
body mass index: the women’s health initiative observational
study. Cancer Epidemiol Biomarkers Prev. 2013;22(12):2412–5.
doi:10.1158/1055-9965.EPI-13-0647.
13. Pothiawala S, Qureshi AA, Li Y, Han J. Obesity and the incidence
of skin cancer in US Caucasians. Cancer Causes Control : CCC.
2012;23(5):717–26. doi:10.1007/s10552-012-9941-x.
14. Sergentanis TN, Antoniadis AG, Gogas HJ, Antonopoulos CN,
Adami HO, Ekbom A, et al. Obesity and risk of malignant mela-
noma: a meta-analysis of cohort and case–control studies. Eur J
Cancer. 2013;49(3):642–57. doi:10.1016/j.ejca.2012.08.028.
397
15. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-
mass index and incidence of cancer: a systematic review and meta-
analysis of prospective observational studies. Lancet.
2008;371(9612):569–78. doi:10.1016/S0140-6736(08)60269-X.
16. Dobbins M, Decorby K, Choi BC. The association between obe-
sity and cancer risk: a meta-analysis of observational studies from
1985 to 2011. ISRN Prev Med. 2013;2013:680536. doi:10.5402
/2013/680536.
17. Veierod MB, Thelle DS, Laake P. Diet and risk of cutaneous ma-
lignant melanoma: a prospective study of 50,757 Norwegian men
and women. Int J Cancer. 1997;71(4):600–4.
18. Olsen CM, Green AC, Zens MS, Stukel TA, Bataille V, Berwick
M, et al. Anthropometric factors and risk of melanoma in women:
a pooled analysis. Int J Cancer. 2008;122(5):1100–8. doi:10.1002
/ijc.23214.
19. Praestegaard C, Kjaer SK, Christensen J, Tjonneland A, Halkjaer
J, Jensen A. Obesity and risks for malignant melanoma and non-
melanoma skin cancer: results from a large Danish prospective
cohort study. J Invest Dermatol. 2015;135(3):901–4. doi:10.1038
/jid.2014.438.
20. Fruhbeck G. Intracellular signalling pathways activated by leptin.
Biochem J. 2006;393(Pt 1):7–20. doi:10.1042/BJ20051578.
21. Courneya KS, Katzmarzyk PT, Bacon E. Physical activity and
obesity in Canadian cancer survivors: population-based estimates
from the 2005 Canadian Community Health Survey. Cancer.
2008;112(11):2475–82. doi:10.1002/cncr.23455.
22. Sahl WJ, Glore S, Garrison P, Oakleaf K, Johnson SD. Basal cell
carcinoma and lifestyle characteristics. Int J Dermatol.
1995;34(6):398–402.
23. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and
trends in obesity among US adults, 1999–2000. JAMA.
2002;288(14):1723–7.
24. Brandon EL, Gu JW, Cantwell L, He Z, Wallace G, Hall JE.
Obesity promotes melanoma tumor growth: role of leptin.
Cancer Biol Ther. 2009;8(19):1871–9.
25. Monteiro CA, Moura EC, Conde WL, Popkin BM.
Socioeconomic status and obesity in adult populations of devel-
oping countries: a review. Bull World Health Organ.
2004;82(12):940–6.
26. Popkin BM, Gordon-Larsen P. The nutrition transition: worldwide
obesity dynamics and their determinants. Int J Obes Relat Metab
Disord. 2004;28 Suppl 3:S2–9. doi:10.1038/sj.ijo.0802804.
27. Li X, Liang L, Zhang M, Song F, Nan H, Wang LE, et al. Obesity-
related genetic variants, human pigmentation, and risk of melano-
ma. Hum Genet. 2013;132(7):793–801. doi:10.1007/s00439-013-
1293-4.
28. Frisancho AR, Wainwright R, Way A. Heritability and compo-
nents of phenotypic expression in skin reflectance of Mestizos
from the Peruvian lowlands. Am J Phys Anthropol. 1981;55(2):
203–8. doi:10.1002/ajpa.1330550207.
29. Harrison GA, Owen JJ. Studies on the inheritance of human skin
colour. Ann Hum Genet. 1964;28:27–37.
30. Turner JB, Kumar A, Koch CA. The effects of indoor and outdoor
temperature on metabolic rate and adipose tissue—the Mississippi
perspective on the obesity epidemic. Rev Endocr Metab Disord.
2016;17(1):61–71. doi:10.1007/s11154-016-9358-z.
31. Tai N, Wong FS, Wen L. The role of gut microbiota in the devel-
opment of type 1, type 2 diabetes mellitus and obesity. Rev Endocr
Metab Disord. 2015;16(1):55–65. doi:10.1007/s11154-015-9309-
0.
32. Gerstenblith MR, Shi J, Landi MT. Genome-wide association
studies of pigmentation and skin cancer: a review and meta-anal-
ysis. Pigment Cell Melanoma Res. 2010;23(5):587–606.
doi:10.1111/j.1755-148X.2010.00730.x.
33. Nan H, Kraft P, Hunter DJ, Han J. Genetic variants in pigmenta-
tion genes, pigmentary phenotypes, and risk of skin cancer in
398
Caucasians. Int J Cancer. 2009;125(4):909–17. doi:10.1002
/ijc.24327.
34. McAllister EJ, Dhurandhar NV, Keith SW, Aronne LJ, Barger J,
Baskin M, et al. Ten putative contributors to the obesity epidemic.
Crit Rev Food Sci Nutr. 2009;49(10):868–913. doi:10.1080
/10408390903372599.
35. Charriere G, Cousin B, Arnaud E, Andre M, Bacou F, Penicaud L,
et al. Preadipocyte conversion to macrophage. Evidence of plas-
ticity. J Biol Chem. 2003;278(11):9850–5. doi:10.1074/jbc.
M210811200.
36. Wang J, Ding N, Li Y, Cheng H, Wang D, Yang Q, et al. Insulin-
like growth factor binding protein 5 (IGFBP5) functions as a tu-
mor suppressor in human melanoma cells. Oncotarget.
2015;6(24):20636–49.
37. Wang H, Ye J. Regulation of energy balance by inflammation:
common theme in physiology and pathology. Rev Endocr Metab
Disord. 2015;16(1):47–54.
38. Kloting N, Bluher M. Adipocyte dysfunction, inflammation and
metabolic syndrome. Rev Endocr Metab Disord. 2014;15(4):277–
87.
39. Ngo HT, Hetland RB, Nygaard UC, Steffensen IL. Genetic and
diet-induced obesity increased intestinal tumorigenesis in the dou-
ble mutant mouse model multiple intestinal neoplasia X obese via
disturbed glucose regulation and inflammation. J Obes.
2015;2015:343479. doi:10.1155/2015/343479.
40. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic
switch in adipose tissue macrophage polarization. J Clin Invest.
2007;117(1):175–84. doi:10.1172/JCI29881.
41. Nguyen MT, Favelyukis S, Nguyen AK, Reichart D, Scott PA,
Jenn A, et al. A subpopulation of macrophages infiltrates hyper-
trophic adipose tissue and is activated by free fatty acids via Toll-
like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem.
2007;282(48):35279–92. doi:10.1074/jbc.M706762200.
42. Strissel KJ, Stancheva Z, Miyoshi H, Perfield 2nd JW, DeFuria J,
Jick Z, et al. Adipocyte death, adipose tissue remodeling, and
obesity complications. Diabetes. 2007;56(12):2910–8.
doi:10.2337/db07-0767.
43. Zaldivar F, McMurray RG, Nemet D, Galassetti P, Mills PJ,
Cooper DM. Body fat and circulating leukocytes in children. Int
J Obes (Lond). 2006;30(6):906–11. doi:10.1038/sj.ijo.0803227.
44. Debnath M, Agrawal S, Agrawal A, Dubey GP. Metaflammatory
responses during obesity: pathomechanism and treatment. Obes
Res Clin Pract. 2015. doi:10.1016/j.orcp.2015.10.012.
45. Lumeng CN, Saltiel AR. Inflammatory links between obesity and
metabolic disease. J Clin Invest. 2011;121(6):2111–7. doi:10.1172
/JCI57132.
46. Shore SA. Environmental perturbations: obesity. Compr Physiol.
2011;1(1):263–82. doi:10.1002/cphy.c100017.
47. Atabek ME, Vatansev H, Erkul I. Oxidative stress in childhood
obesity. J Pediatr Endocrinol Metab. 2004;17(8):1063–8.
48. Bakker SJ RGIJ, Teerlink T, Westerhoff HV, Gans RO, Heine RJ.
Cytosolic triglycerides and oxidative stress in central obesity: the
missing link between excessive atherosclerosis, endothelial dys-
function, and beta-cell failure? Atherosclerosis. 2000;148(1):17–
21.
49. Keaney Jr JF, Larson MG, Vasan RS, Wilson PW, Lipinska I,
Corey D, et al. Obesity and systemic oxidative stress: clinical
correlates of oxidative stress in the Framingham Study.
Arterioscler Thromb Vasc Biol. 2003;23(3):434–9. doi:10.1161
/01.ATV.0000058402.34138.11.
50. Lee YS, Kim AY, Choi JW, Kim M, Yasue S, Son HJ, et al.
Dysregulation of adipose glutathione peroxidase 3 in obesity con-
tributes to local and systemic oxidative stress. Mol Endocrinol.
2008;22(9):2176–89. doi:10.1210/me.2008-0023.
51. Hernandez AR, Boada LD, Almeida-Gonzalez M, Mendoza Z,
Ruiz-Suarez N, Valeron PF, et al. An estimation of the
Rev Endocr Metab Disord (2016) 17:389–403
carcinogenic risk associated with the intake of multiple relevant
carcinogens found in meat and charcuterie products. Sci Total
Environ. 2015;514:33–41. doi:10.1016/j.scitotenv.2015.01.108.
52. Schut HA, Snyderwine EG. DNA adducts of heterocyclic amine
food mutagens: implications for mutagenesis and carcinogenesis.
Carcinogenesis. 1999;20(3):353–68.
53. Pei YF, Tian Q, Zhang L, Deng HW. Exploring the major sources
and extent of heterogeneity in a genome-wide association meta-
analysis. Ann Hum Genet. 2015. doi:10.1111/ahg.12143.
54. Holmes L, LaHurd A, Wasson E, McClarin L, Dabney K. Racial
and ethnic heterogeneity in the association between total choles-
terol and pediatric obesity. Int J Environ Res Public Health.
2015;13(1). doi:10.3390/ijerph13010019.
55. Perl A. mTOR activation is a biomarker and a central pathway to
autoimmune disorders, cancer, obesity, and aging. Ann N Y Acad
Sci. 2015;1346(1):33–44. doi:10.1111/nyas.12756.
56. Cowen S, McLaughlin SL, Hobbs G, Coad J, Martin KH, Olfert
IM, et al. High-fat, high-calorie diet enhances mammary carcino-
genesis and local inflammation in MMTV-PyMT mouse model of
breast cancer. Cancers (Basel). 2015;7(3):1125–42. doi:10.3390
/cancers7030828.
57. Crujeiras AB, Cabia B, Carreira MC, Amil M, Cueva J, Andrade
S, et al. Secreted factors derived from obese visceral adipose tissue
regulate the expression of breast malignant transformation genes.
Int J Obes (Lond). 2015. doi:10.1038/ijo.2015.208.
58. Gorlach A, Dimova EY, Petry A, Martinez-Ruiz A, Hernansanz-
Agustin P, Rolo AP, et al. Reactive oxygen species, nutrition,
hypoxia and diseases: problems solved? Redox Biol. 2015;6:
372–85. doi:10.1016/j.redox.2015.08.016.
59. Hasan S, Suhail N, Bilal N, Ashraf GM, Zaidi SK, AlNohair S,
et al. Chronic unpredictable stress deteriorates the chemopreven-
tive efficacy of pomegranate through oxidative stress pathway.
Tumour Biol. 2015. doi:10.1007/s13277-015-4469-9.
60. Manna P, Jain SK. Obesity, oxidative stress, adipose tissue dys-
function, and the associated health risks: causes and therapeutic
strategies. Metab Syndr Relat Disord. 2015;13(10):423–44.
doi:10.1089/met.2015.0095.
61. Hunsche C, Hernandez O, De la Fuente M. Impaired immune
response in old mice suffering from obesity and premature
immunosenescence in adulthood. J Gerontol A Biol Sci Med
Sci. 2015. doi:10.1093/gerona/glv082.
62. Meyskens Jr FL, Farmer PJ, Anton-Culver H. Etiologic pathogen-
esis of melanoma: a unifying hypothesis for the missing attribut-
able risk. Clin Cancer Res : Off J Am Assoc Cancer Res.
2004;10(8):2581–3.
63. Caslin HL, Franco RL, Crabb EB, Huang CJ, Bowen MK,
Acevedo EO. The effect of obesity on inflammatory cytokine
and leptin production following acute mental stress.
Psychophysiology. 2015. doi:10.1111/psyp.12568.
64. Gogas H, Trakatelli M, Dessypris N, Terzidis A, Katsambas A,
Chrousos GP, et al. Melanoma risk in association with serum
leptin levels and lifestyle parameters: a case–control study. Ann
Oncol. 2008;19(2):384–9. doi:10.1093/annonc/mdm464.
65. Dayakar A, Chandrasekaran S, Veronica J, Maurya RS. Leptin
induces the phagocytosis and protective immune response in
Leishmania donovani infected THP-1 cell line and human
PBMCs. Exp Parasitol. 2015. doi:10.1016/j.exppara.2015.12.002.
66. Huang CJ, McAllister MJ, Slusher AL, Webb HE, Mock JT,
Acevedo EO. Obesity-related oxidative stress: the impact of phys-
ical activity and diet manipulation. Sports Med Open. 2015;1(1):
32. doi:10.1186/s40798-015-0031-y.
67. Mizutani H, Fukushima S, Masuguchi S, Yamashita J, Miyashita
A, Nakahara S, et al. Serum levels of leptin receptor in patients
with malignant melanoma as a new tumor marker. Exp Dermatol.
2013;22(11):748–9. doi:10.1111/exd.12238.
Rev Endocr Metab Disord (2016) 17:389–403
68. Chirumbolo S. The role of vitamin D towards immune tolerance in
white adipose tissue (WAT). Endocr Metab Immune Disord Drug
Targets. 2015;15(4):277–87.
69. Yao Y, Zhu L, He L, Duan Y, Liang W, Nie Z, et al. A meta-
analysis of the relationship between vitamin D deficiency and
obesity. Int J Clin Exp Med. 2015;8(9):14977–84.
70. Lagunova Z, Porojnicu AC, Grant WB, Bruland O, Moan JE.
Obesity and increased risk of cancer: does decrease of serum 25-
hydroxyvitamin D level with increasing body mass index explain
some of the association? Mol Nutr Food Res. 2010;54(8):1127–
33. doi:10.1002/mnfr.200900512.
71. Kremer R, Campbell PP, Reinhardt T, Gilsanz V. Vitamin D status
and its relationship to body fat, final height, and peak bone mass in
young women. J Clin Endocrinol Metab. 2009;94(1):67–73.
doi:10.1210/jc.2008-1575.
72. Bikle DD. Vitamin D, and the skin: physiology and pathophysi-
ology. Rev Endocr Metab Disord. 2012;13(1):3–19.
73. Holick MF. Vitamin D: importance in the prevention of cancers,
type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr.
2004;79(3):362–71.
74. Lackey DE, Olefsky JM. Regulation of metabolism by the innate
immune system. Nat Rev Endocrinol. 2016;12(1):15–28.
doi:10.1038/nrendo.2015.189.
75. Zeyda M, Stulnig TM. Adipose tissue macrophages. Immunol
Lett. 2007;112(2):61–7. doi:10.1016/j.imlet.2007.07.003.
76. De Pergola G, Silvestris F. Obesity as a major risk factor for
cancer. J Obes. 2013;2013:291546. doi:10.1155/2013/291546.
77. Saraiya A, Al-Shoha A, Brodell RT. Hyperinsulinemia associated
with acanthosis nigricans, finger pebbles, acrochordons, and the
sign of Leser-Trelat. Endocr Pract. 2013;19(3):522–5.
doi:10.4158/EP12192.RA.
78. East HE, Subauste JS, Gandhi A, Koch CA. About secondary
causes of diabetes mellitus. J Miss State Med Assoc.
2012;53(11):380–3.
79. Cheng S, Gomez K, Serri O, Chik C, Ezzat S. The role of diabetes
in acromegaly associated neoplasia. PLoS One. 2015;10(5),
e0127276. doi:10.1371/journal.pone.0127276.
80. Su Y, Carey LC, Rose JC, Pulgar VM. Leptin alters adrenal re-
sponsiveness by decreasing expression of ACTH-R, StAR, and
P450c21 in hypoxemic fetal sheep. Reprod Sci. 2012;19(10):
1075–84. doi:10.1177/1933719112442246.
81. Ellerhorst JA, Diwan AH, Dang SM, Uffort DG, Johnson MK,
Cooke CP, et al. Promotion of melanoma growth by the metabolic
hormone leptin. Oncol Rep. 2010;23(4):901–7.
82. de Vries E, Coebergh JW. Cutaneous malignant melanoma in
Europe. Eur J Cancer. 2004;40(16):2355–66. doi:10.1016/j.
ejca.2004.06.003.
83. Lasithiotakis KG, Leiter U, Gorkievicz R, Eigentler T, Breuninger
H, Metzler G, et al. The incidence and mortality of cutaneous
melanoma in Southern Germany: trends by anatomic site and
pathologic characteristics, 1976 to 2003. Cancer. 2006;107(6):
1331–9. doi:10.1002/cncr.22126.
84. Mansson-Brahme E, Johansson H, Larsson O, Rutqvist LE,
Ringborg U. Trends in incidence of cutaneous malignant melano-
ma in a Swedish population 1976–1994. Acta Oncol. 2002;41(2):
138–46.
85. Stang A, Pukkala E, Sankila R, Soderman B, Hakulinen T. Time
trend analysis of the skin melanoma incidence of Finland from
1953 through 2003 including 16,414 cases. Int J Cancer.
2006;119(2):380–4. doi:10.1002/ijc.21836.
86. Linos E, Swetter SM, Cockburn MG, Colditz GA, Clarke CA.
Increasing burden of melanoma in the United States. J Invest
Dermatol. 2009;129(7):1666–74. doi:10.1038/jid.2008.423.
87. Ortiz CA, Goodwin JS, Freeman JL. The effect of socioeconomic
factors on incidence, stage at diagnosis and survival of cutaneous
melanoma. Med Sci Monit. 2005;11(5):RA163–72.
399
88. Pollitt RA, Clarke CA, Shema SJ, Swetter SM. California
Medicaid enrollment and melanoma stage at diagnosis: a
population-based study. Am J Prev Med. 2008;35(1):7–13.
doi:10.1016/j.amepre.2008.03.026.
89. Roetzheim RG, Pal N, Tennant C, Voti L, Ayanian JZ, Schwabe A,
et al. Effects of health insurance and race on early detection of
cancer. J Natl Cancer Inst. 1999;91(16):1409–15.
90. Diffey B. Climate change, ozone depletion and the impact on
ultraviolet exposure of human skin. Phys Med Biol.
2004;49(1):R1–11.
91. Welch HG, Woloshin S, Schwartz LM. Skin biopsy rates and
incidence of melanoma: population based ecological study.
BMJ. 2005;331(7515):481. doi:10.1136/bmj.38516.649537.E0.
92. Hall HI, Jamison P, Fulton JP, Clutter G, Roffers S, Parrish P.
Reporting cutaneous melanoma to cancer registries in the United
States. J Am Acad Dermatol. 2003;49(4):624–30.
93. Swerlick RA, Chen S. The melanoma epidemic. Is increased sur-
veillance the solution or the problem? Arch Dermatol.
1996;132(8):881–4.
94. Swerlick RA, Chen S. The melanoma epidemic: more apparent
than real? Mayo Clin Proc. 1997;72(6):559–64. doi:10.1016
/S0025-6196(11)63306-5.
95. Olsen CM, Carroll HJ, Whiteman DC. Estimating the attributable
fraction for cancer: a meta-analysis of nevi and melanoma. Cancer
Prev Res (Phila). 2010;3(2):233–45. doi:10.1158/1940-6207.
CAPR-09-0108.
96. Gandini S, Sera F, Cattaruzza MS, Pasquini P, Zanetti R, Masini C,
et al. Meta-analysis of risk factors for cutaneous melanoma: III.
Family history, actinic damage and phenotypic factors. Eur J
Cancer. 2005;41(14):2040–59. doi:10.1016/j.ejca.2005.03.034.
97. Wheless L, Black J, Alberg AJ. Nonmelanoma skin cancer and the
risk of second primary cancers: a systematic review. Cancer
Epidemiol Biomarkers Prev. 2010;19(7):1686–95. doi:10.1158
/1055-9965.EPI-10-0243.
98. Chen ST, Geller AC, Tsao H. Update on the epidemiology of
melanoma. Curr Dermatol Rep. 2013;2(1):24–34. doi:10.1007
/s13671-012-0035-5.
99. Pappo AS, Armstrong GT, Liu W, Srivastava DK, McDonald A,
Leisenring WM, et al. Melanoma as a subsequent neoplasm in
adult survivors of childhood cancer: a report from the childhood
cancer survivor study. Pediatr Blood Cancer. 2013;60(3):461–6.
doi:10.1002/pbc.24266.
100. Gandini S, Sera F, Cattaruzza MS, Pasquini P, Picconi O, Boyle P,
et al. Meta-analysis of risk factors for cutaneous melanoma: II.
Sun exposure. Eur J Cancer. 2005;41(1):45–60. doi:10.1016/j.
ejca.2004.10.016.
101. Rigel DS, Rigel EG, Rigel AC. Effects of altitude and latitude on
ambient UVB radiation. J Am Acad Dermatol. 1999;40(1):114–6.
102. Bulliard JL. Site-specific risk of cutaneous malignant melanoma
and pattern of sun exposure in New Zealand. Int J Cancer.
2000;85(5):627–32.
103. Parisi AV, Kimlin MG, Lester R, Turnbull D. Lower body ana-
tomical distribution of solar ultraviolet radiation on the human
form in standing and sitting postures. J Photochem Photobiol B.
2003;69(1):1–6.
104. Reed KB, Brewer JD, Lohse CM, Bringe KE, Pruitt CN, Gibson
LE. Increasing incidence of melanoma among young adults: an
epidemiological study in Olmsted County. Minnesota Mayo Clin
Proc. 2012;87(4):328–34. doi:10.1016/j.mayocp.2012.01.010.
105. Stryker WS, Stampfer MJ, Stein EA, Kaplan L, Louis TA, Sober
A, et al. Diet, plasma levels of beta-carotene and alpha-tocopherol,
and risk of malignant melanoma. Am J Epidemiol. 1990;131(4):
597–611.
106. Bain C, Green A, Siskind V, Alexander J, Harvey P. Diet and
melanoma. An exploratory case–control study. Ann Epidemiol.
1993;3(3):235–8.
400
107. Millen AE, Tucker MA, Hartge P, Halpern A, Elder DE, Guerry D,
et al. Diet and melanoma in a case–control study. Cancer
Epidemiol Biomarkers Prev. 2004;13(6):1042–51.
108. Meyskens Jr FL, Farmer PJ, Anton-Culver H. Diet and melanoma
in a case–control study. Cancer Epidemiol Biomarkers Prev.
2005;14(1):293.
109. Le Marchand L, Saltzman BS, Hankin JH, Wilkens LR, Franke
AA, Morris SJ, et al. Sun exposure, diet, and melanoma in Hawaii
Caucasians. Am J Epidemiol. 2006;164(3):232–45. doi:10.1093
/aje/kwj115.
110. Nicolopoulou-Stamati P, Hens L, Sasco AJ. Cosmetics as endo-
crine disruptors: are they a health risk? Rev Endocr Metab Disord.
2015;16(4):373–83.
111. Holland KT, Bojar RA. Cosmetics: what is their influence on the
skin microflora? Am J Clin Dermatol. 2002;3(7):445–9.
112. Karpuzoglu E, Holladay SD, Gogal Jr RM. Parabens: potential
impact of low-affinity estrogen receptor binding chemicals on hu-
man health. J Toxicol Environ Health B Crit Rev. 2013;16(5):321–
35. doi:10.1080/10937404.2013.809252.
113. Gandini S, Iodice S, Koomen E, Di Pietro A, Sera F, Caini S.
Hormonal and reproductive factors in relation to melanoma in
women: current review and meta-analysis. Eur J Cancer.
2011;47(17):2607–17. doi:10.1016/j.ejca.2011.04.023.
114. Ward EM, Burnett CA, Ruder A, Davis-King K. Industries and
cancer. Cancer Causes Control. 1997;8(3):356–70.
115. Sinks T, Steele G, Smith AB, Watkins K, Shults RA. Mortality
among workers exposed to polychlorinated biphenyls. Am J
Epidemiol. 1992;136(4):389–98.
116. Loomis D, Browning SR, Schenck AP, Gregory E, Savitz DA.
Cancer mortality among electric utility workers exposed to
polychlorinated biphenyls. Occup Environ Med. 1997;54(10):
720–8.
117. Robinson CF, Petersen M, Palu S. Mortality patterns among elec-
trical workers employed in the U.S. construction industry, 1982–
1987. Am J Ind Med. 1999;36(6):630–7.
118. Nelemans PJ, Scholte R, Groenendal H, Kiemeney LA, Rampen
FH, Ruiter DJ, et al. Melanoma and occupation: results of a case–
control study in The Netherlands. Br J Ind Med. 1993;50(7):642–
6.
119. Gantz I, Fong TM. The melanocortin system. Am J Physiol
Endocrinol Metab. 2003;284(3):E468–74. doi:10.1152
/ajpendo.00434.2002.
120. Danforth CH. Hereditary adiposity in mice. Obes Res. 1996;4(1):
96–100.
121. Dickies MM. A new viable yellow mutation in the house mouse. J
Hered. 1962;53:84–6.
122. Heston WE, Vlahakis G. Influence of the Ay gene on mammary-
gland tumors, hepatomas, and normal growth in mice. J Natl
Cancer Inst. 1961;26:969–83.
123. Heston WE, Vlahakis G. C3H-Avy—a high hepatoma and high
mammary tumor strain of mice. J Natl Cancer Inst. 1968;40(6):
1161–6.
124. Yen TT, Gill AM, Frigeri LG, Barsh GS, Wolff GL. Obesity,
diabetes, and neoplasia in yellow A(vy)/- mice: ectopic expression
of the agouti gene. FASEB J. 1994;8(8):479–88.
125. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A.
Severe early-onset obesity, adrenal insufficiency and red hair pig-
mentation caused by POMC mutations in humans. Nat Genet.
1998;19(2):155–7. doi:10.1038/509.
126. Millington GW. Proopiomelanocortin (POMC): the cutaneous
roles of its melanocortin products and receptors. Clin Exp
D e r m a t o l . 2 0 0 6 ; 3 1 ( 3 ) : 4 0 7 – 1 2 . d o i : 1 0 . 1111 / j . 1 3 6 5 -
2230.2006.02128.x.
127. Ramachandrappa S, Farooqi IS. Genetic approaches to under-
standing human obesity. J Clin Invest. 2011;121(6):2080–6.
doi:10.1172/JCI46044.
Rev Endocr Metab Disord (2016) 17:389–403
128. D’Orazio JA, Nobuhisa T, Cui R, Arya M, Spry M, Wakamatsu K,
et al. Topical drug rescue strategy and skin protection based on the
role of Mc1r in UV-induced tanning. Nature. 2006;443(7109):
340–4. doi:10.1038/nature05098.
129. Cui R, Widlund HR, Feige E, Lin JY, Wilensky DL, Igras VE,
et al. Central role of p53 in the suntan response and pathologic
hyperpigmentation. Cell. 2007;128(5):853–64. doi:10.1016/j.
cell.2006.12.045.
130. Sato HNY, Chrousos GP, Ichihashi M, Funasak Y. The expression
of corticotropin-releasing hormone in melanoma. Pigment Cell
Res. 2002;15(2):98–103.
131. Millington GW. The role of proopiomelanocortin (POMC)
neurones in feeding behaviour. Nutr Metab (Lond). 2007;4:18.
doi:10.1186/1743-7075-4-18.
132. Sharma SD, Katiyar SK. Leptin deficiency-induced obesity exac-
erbates ultraviolet B radiation-induced cyclooxygenase-2 expres-
sion and cell survival signals in ultraviolet B-irradiated mouse
skin. Toxicol Appl Pharmacol. 2010;244(3):328–35. doi:10.1016
/j.taap.2010.01.010.
133. Akbani R, Akdemir KC, Aksoy BA, Albert M, Ally A, Amin SB,
et al. Genomic classification of cutaneous melanoma. Cell.
2015;161(7):1681–96. doi:10.1016/j.cell.2015.05.044.
134. Garofalo C, Surmacz E. Leptin and cancer. J Cell Physiol.
2006;207(1):12–22. doi:10.1002/jcp.20472.
135. Tessitore L, Vizio B, Jenkins O, De Stefano I, Ritossa C, Argiles
JM, et al. Leptin expression in colorectal and breast cancer pa-
tients. Int J Mol Med. 2000;5(4):421–6.
136. Petridou E, Belechri M, Dessypris N, Koukoulomatis P,
Diakomanolis E, Spanos E, et al. Leptin and body mass index
in relation to endometrial cancer risk. Ann Nutr Metab.
2002;46(3–4):147–51.
137. Stattin P, Palmqvist R, Soderberg S, Biessy C, Ardnor B,
Hallmans G, et al. Plasma leptin and colorectal cancer risk: a
prospective study in Northern Sweden. Oncol Rep. 2003;10(6):
2015–21.
138. Arnardottir ES, Maislin G, Jackson N, Schwab RJ, Benediktsdottir
B, Teff K, et al. The role of obesity, different fat compartments and
sleep apnea severity in circulating leptin levels: the Icelandic Sleep
Apnea Cohort study. Int J Obes (Lond). 2013;37(6):835–42.
doi:10.1038/ijo.2012.138.
139. Leroy P, Dessolin S, Villageois P, Moon BC, Friedman JM,
Ailhaud G, et al. Expression of ob gene in adipose cells.
Regulation by insulin. J Biol Chem. 1996;271(5):2365–8.
140. Zhang HH, Kumar S, Barnett AH, Eggo MC. Tumour necrosis
factor-alpha exerts dual effects on human adipose leptin synthesis
and release. Mol Cell Endocrinol. 2000;159(1–2):79–88.
141. Dagogo-Jack S, Selke G, Melson AK, Newcomer JW. Robust
leptin secretory responses to dexamethasone in obese subjects. J
Clin Endocrinol Metab. 1997;82(10):3230–3. doi:10.1210
/jcem.82.10.4154.
142. Machinal-Quelin F, Dieudonne MN, Pecquery R, Leneveu MC,
Giudicelli Y. Direct in vitro effects of androgens and estrogens on
ob gene expression and leptin secretion in human adipose tissue.
Endocrine. 2002;18(2):179–84. doi:10.1385/ENDO:18:2:179.
143. Fain JN, Leffler CW, Bahouth SW. Eicosanoids as endogenous
regulators of leptin release and lipolysis by mouse adipose tissue
in primary culture. J Lipid Res. 2000;41(10):1689–94.
144. Oba J, Wei W, Gershenwald JE, Johnson MM, Wyatt CM,
Ellerhorst JA, et al. Elevated serum leptin levels are associated
with an increased risk of sentinel lymph node metastasis in cuta-
neous melanoma. Medicine (Baltimore). 2016;95(11), e3073.
doi:10.1097/MD.0000000000003073.
145. Jung JI, Cho HJ, Jung YJ, Kwon SH, Her S, Choi SS, et al. High-
fat diet-induced obesity increases lymphangiogenesis and lymph
node metastasis in the B16F10 melanoma allograft model: roles of
Rev Endocr Metab Disord (2016) 17:389–403
adipocytes and M2-macrophages. Int J Cancer. 2015;136(2):258–
70. doi:10.1002/ijc.28983.
146. McMurphy T, Xiao R, Magee D, Slater A, Zabeau L, Tavernier J,
et al. The anti-tumor activity of a neutralizing nanobody targeting
leptin receptor in a mouse model of melanoma. PLoS ONE.
2014;9(2), e89895. doi:10.1371/journal.pone.0089895.
147. Emilsson V, Liu YL, Cawthorne MA, Morton NM, Davenport M.
Expression of the functional leptin receptor mRNA in pancreatic
islets and direct inhibitory action of leptin on insulin secretion.
Diabetes. 1997;46(2):313–6.
148. Kulkarni RN, Wang ZL, Wang RM, Hurley JD, Smith DM, Ghatei
MA, et al. Leptin rapidly suppresses insulin release from
insulinoma cells, rat and human islets, and in vivo, in mice. J
Clin Invest. 1997;100(11):2729–36. doi:10.1172/JCI119818.
149. Morris DL, Rui L. Recent advances in understanding leptin sig-
naling and leptin resistance. Am J Physiol Endocrinol Metab.
2009;297(6):E1247–59. doi:10.1152/ajpendo.00274.2009.
150. Wang MY, Lee Y, Unger RH. Novel form of lipolysis induced by
leptin. J Biol Chem. 1999;274(25):17541–4.
151. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P.
Recombinant mouse OB protein: evidence for a peripheral signal
linking adiposity and central neural networks. Science.
1995;269(5223):546–9.
152. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT,
Rabinowitz D, et al. Weight-reducing effects of the plasma protein
encoded by the obese gene. Science. 1995;269(5223):543–6.
153. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D,
Boone T, et al. Effects of the obese gene product on body weight
regulation in ob/ob mice. Science. 1995;269(5223):540–3.
154. Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM,
Burgett SG, Craft L, et al. The role of neuropeptide Y in the
antiobesity action of the obese gene product. Nature.
1995;377(6549):530–2. doi:10.1038/377530a0.
155. Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova
I, Goldman WH, et al. Decreased cerebrospinal-fluid/serum leptin
ratio in obesity: a possible mechanism for leptin resistance.
Lancet. 1996;348(9021):159–61.
156. El-Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C, Flier JS.
Two defects contribute to hypothalamic leptin resistance in mice
with diet-induced obesity. J Clin Invest. 2000;105(12):1827–32.
doi:10.1172/JCI9842.
157. Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte Jr D.
Cerebrospinal fluid leptin levels: relationship to plasma levels
and to adiposity in humans. Nat Med. 1996;2(5):589–93.
158. Belouzard S, Delcroix D, Rouille Y. Low levels of expression
of leptin receptor at the cell surface result from constitutive
endocytosis and intracellular retention in the biosynthetic
p a t h w a y. J B i o l C h e m . 2 0 0 4 ; 2 7 9 ( 2 7 ) : 2 8 4 9 9 – 5 0 8 .
doi:10.1074/jbc.M400508200.
159. Diano S, Kalra SP, Horvath TL. Leptin receptor immunoreactivity
is associated with the Golgi apparatus of hypothalamic neurons
and glial cells. J Neuroendocrinol. 1998;10(9):647–50.
160. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H,
Wareham NJ, et al. Congenital leptin deficiency is associated with
severe early-onset obesity in humans. Nature. 1997;387(6636):
903–8. doi:10.1038/43185.
161. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin
missense mutation associated with hypogonadism and morbid
obesity. Nat Genet. 1998;18(3):213–5. doi:10.1038/ng0398-213.
162. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman
JM. Positional cloning of the mouse obese gene and its human
homologue. Nature. 1994;372(6505):425–32. doi:10.1038
/372425a0.
163. Martin SS, Qasim A, Reilly MP. Leptin resistance: a possible
interface of inflammation and metabolism in obesity-related
401
cardiovascular disease. J Am Coll Cardiol. 2008;52(15):1201–
10. doi:10.1016/j.jacc.2008.05.060.
164. Mantzoros CS, Liolios AD, Tritos NA, Kaklamani VG,
Doulgerakis DE, Griveas I, et al. Circulating insulin concentra-
tions, smoking, and alcohol intake are important independent pre-
dictors of leptin in young healthy men. Obes Res. 1998;6(3):179–
86.
165. Traish AM, Zitzmann M. The complex and multifactorial relation-
ship between testosterone deficiency (TD), obesity and vascular
disease. Rev Endocr Metab Disord. 2015;16(3):249–68.
doi:10.1007/s11154-015-9323-2.
166. Ullah MI, Washington T, Kazi M, Tamanna S, Koch CA.
Testosterone deficiency as a risk factor for cardiovascular disease.
Horm Metab Res. 2011;43(03):153–64.
167. Coppari R, Bjorbaek C. Leptin revisited: its mechanism of action
and potential for treating diabetes. Nat Rev Drug Discov.
2012;11(9):692–708. doi:10.1038/nrd3757.
168. Stanley BG, Leibowitz SF. Neuropeptide Y injected in the
paraventricular hypothalamus: a powerful stimulant of feeding
behavior. Proc Natl Acad Sci U S A. 1985;82(11):3940–3.
169. Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D, et al.
Endoplasmic reticulum stress plays a central role in development
of leptin resistance. Cell Metab. 2009;9(1):35–51. doi:10.1016/j.
cmet.2008.12.004.
170. Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D.
Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutri-
tion to energy imbalance and obesity. Cell. 2008;135(1):61–73.
doi:10.1016/j.cell.2008.07.043.
171. Ogimoto K, Harris Jr MK, Wisse BE. MyD88 is a key mediator of
anorexia, but not weight loss, induced by lipopolysaccharide and
interleukin-1 beta. Endocrinology. 2006;147(9):4445–53.
doi:10.1210/en.2006-0465.
172. Ozcan U, Ozcan L, Yilmaz E, Duvel K, Sahin M, Manning BD,
et al. Loss of the tuberous sclerosis complex tumor suppressors
triggers the unfolded protein response to regulate insulin signaling
and apoptosis. Mol Cell. 2008;29(5):541–51. doi:10.1016/j.
molcel.2007.12.023.
173. Hosoi T, Sasaki M, Miyahara T, Hashimoto C, Matsuo S, Yoshii
M, et al. Endoplasmic reticulum stress induces leptin resistance.
M o l P h a r m a c o l . 2 0 0 8 ; 7 4 ( 6 ) : 1 6 1 0 – 9 . d o i : 1 0 . 11 2 4
/mol.108.050070.
174. Lam QL, Lu L. Role of leptin in immunity. Cell Mol Immunol.
2007;4(1):1–13.
175. Chen K, Li F, Li J, Cai H, Strom S, Bisello A, et al. Induction of
leptin resistance through direct interaction of C-reactive protein
with leptin. Nat Med. 2006;12(4):425–32. doi:10.1038/nm1372.
176. Amjadi F, Javanmard SH, Zarkesh-Esfahani H, Khazaei M,
Narimani M. Leptin promotes melanoma tumor growth in mice
related to increasing circulating endothelial progenitor cells num-
bers and plasma NO production. J Exp Clin Cancer Res. 2011;30:
21. doi:10.1186/1756-9966-30-21.
177. Dome B, Hendrix MJ, Paku S, Tovari J, Timar J. Alternative
vascularization mechanisms in cancer: pathology and therapeutic
implications. Am J Pathol. 2007;170(1):1–15. doi:10.2353
/ajpath.2007.060302.
178. Gonzalez RR, Cherfils S, Escobar M, Yoo JH, Carino C, Styer
AK, et al. Leptin signaling promotes the growth of mammary
tumors and increases the expression of vascular endothelial
growth factor (VEGF) and its receptor type two (VEGF-R2). J
Biol Chem. 2006;281(36):26320–8. doi:10.1074/jbc.
M601991200.
179. Ribatti D, Nico B, Belloni AS, Vacca A, Roncali L, Nussdorfer
GG. Angiogenic activity of leptin in the chick embryo chorioal-
lantoic membrane is in part mediated by endogenous fibroblast
growth factor-2. Int J Mol Med. 2001;8(3):265–8.
402
180. Lago R, Gomez R, Lago F, Gomez-Reino J, Gualillo O. Leptin
beyond body weight regulation—current concepts concerning its
role in immune function and inflammation. Cell Immunol.
2008;252(1–2):139–45. doi:10.1016/j.cellimm.2007.09.004.
181. Artwohl M, Roden M, Holzenbein T, Freudenthaler A, Waldhausl
W, Baumgartner-Parzer SM. Modulation by leptin of proliferation
and apoptosis in vascular endothelial cells. Int J Obes Relat Metab
Disord. 2002;26(4):577–80.
182. Ahima RS, Flier JS. Leptin. Annu Rev Physiol. 2000;62:413–37.
doi:10.1146/annurev.physiol.62.1.413.
183. Grosfeld A, Andre J, Hauguel-De Mouzon S, Berra E, Pouyssegur
J, Guerre-Millo M. Hypoxia-inducible factor 1 transactivates the
human leptin gene promoter. J Biol Chem. 2002;277(45):42953–
7. doi:10.1074/jbc.M206775200.
184. Brakenhielm E, Veitonmaki N, Cao R, Kihara S, Matsuzawa Y,
Zhivotovsky B, et al. Adiponectin-induced antiangiogenesis and
antitumor activity involve caspase-mediated endothelial cell apo-
ptosis. Proc Natl Acad Sci U S A. 2004;101(8):2476–81.
185. Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A,
Ouchi N, et al. Adiponectin, a new member of the family of sol-
uble defense collagens, negatively regulates the growth of
myelomonocytic progenitors and the functions of macrophages.
Blood. 2000;96(5):1723–32.
186. Kang JH, Lee YY, Yu BY, Yang BS, Cho KH, Yoon DK, et al.
Adiponectin induces growth arrest and apoptosis of MDA-MB-
231 breast cancer cell. Arch Pharm Res. 2005;28(11):1263–9.
187. Ogunwobi OO, Beales IL. Adiponectin stimulates proliferation
and cytokine secretion in colonic epithelial cells. Regul Pept.
2006;134(2–3):105–13. doi:10.1016/j.regpep.2006.02.001.
188. Bub JD, Miyazaki T, Iwamoto Y. Adiponectin as a growth inhib-
itor in prostate cancer cells. Biochem Biophys Res Commun.
2006;340(4):1158–66. doi:10.1016/j.bbrc.2005.12.103.
189. Arditi JD, Venihaki M, Karalis KP, Chrousos GP. Antiproliferative
effect of adiponectin on MCF7 breast cancer cells: a potential
hormonal link between obesity and cancer. Horm Metab Res.
2007;39(1):9–13. doi:10.1055/s-2007-956518.
190. Mantzoros CS, Trakatelli M, Gogas H, Dessypris N, Stratigos A,
Chrousos GP, et al. Circulating adiponectin levels in relation to
melanoma: a case–control study. Eur J Cancer. 2007;43(9):1430–
6. doi:10.1016/j.ejca.2007.03.026.
191. Gallagher EJ, Fierz Y, Ferguson RD, LeRoith D. The pathway
from diabetes and obesity to cancer, on the route to targeted ther-
apy. Endocr Pract. 2010;16(5):864–73. doi:10.4158/EP10098.
RA.
192. Moore T, Carbajal S, Beltran L, Perkins SN, Yakar S, Leroith D,
et al. Reduced susceptibility to two-stage skin carcinogenesis in
mice with low circulating insulin-like growth factor I levels.
Cancer Res. 2008;68(10):2680–8.
193. Sadagurski MYS, Weingarten G, Holzenberger M, Rhodes CJ,
Breitkreutz D, Leroith D, et al. Insulin-like growth factor 1 recep-
tor signaling regulates skin development and inhibits skin
keratinocyte differentiation. Mol Cell Biol. 2006;26(7):2675–87.
194. Chi M, Ye Y, Zhang XD, Chen J. Insulin induces drug resistance
in melanoma through activation of the PI3K/Akt pathway. Drug
Des Devel Ther. 2014;8:255–62. doi:10.2147/DDDT.S53568.
195. Kucera R, Treskova I, Vrzalova J, Svobodova S, Topolcan O,
Fuchsova R, et al. Evaluation of IGF1 serum levels in malignant
melanoma and healthy subjects. Anticancer Res. 2014;34(9):
5217–20.
196. Naspi A, Panasiti V, Abbate F, Roberti V, Devirgiliis V, Curzio M,
et al. Insulin-like-growth-factor-binding-protein-3 (IGFBP-3) con-
trasts melanoma progression in vitro and in vivo. PLoS One.
2014;9(6), e98641. doi:10.1371/journal.pone.0098641.
197. Jones SA, Morand EF. Glucocorticoids in 2015: new answers to
old problems. Nat Rev Rheumatol. 2015. doi:10.1038
/nrrheum.2015.176.
Rev Endocr Metab Disord (2016) 17:389–403
198. Bhakoo HS, Milholland RJ, Lopez R, Karakousis C, Rosen F.
High incidence and characterization of glucocorticoid receptors
in human malignant melanoma. J Natl Cancer Inst. 1981;66(1):
21–5.
199. Dobos J, Kenessey I, Timar J, Ladanyi A. Glucocorticoid receptor
expression and antiproliferative effect of dexamethasone on hu-
man melanoma cells. Pathol Oncol Res. 2011;17(3):729–34.
doi:10.1007/s12253-011-9377-8.
200. Spencer SJ, Tilbrook A. The glucocorticoid contribution to obesi-
t y. S t r e s s . 2 0 11 ; 1 4 ( 3 ) : 2 3 3 – 4 6 . d o i : 1 0 . 3 1 0 9
/10253890.2010.534831.
201. Livingstone DE, Jones GC, Smith K, Jamieson PM, Andrew R,
Kenyon CJ, et al. Understanding the role of glucocorticoids in
obesity: tissue-specific alterations of corticosterone metabolism
in obese Zucker rats. Endocrinology. 2000;141(2):560–3.
doi:10.1210/endo.141.2.7297.
202. Shoag J, Haq R, Zhang M, Liu L, Rowe GC, Jiang A, et al. PGC-1
coactivators regulate MITF and the tanning response. Mol Cell.
2013;49(1):145–57. doi:10.1016/j.molcel.2012.10.027.
203. Price RA, Li WD, Zhao H. FTO gene SNPs associated with ex-
treme obesity in cases, controls and extremely discordant sister
pairs. BMC Med Genet. 2008;9:4. doi:10.1186/1471-2350-9-4.
204. Ghosh S, Murinova L, Trnovec T, Loffredo CA, Washington K,
Mitra PS, et al. Biomarkers linking PCB exposure and obesity.
Curr Pharm Biotechnol. 2014;15(11):1058–68.
205. De Coster S, van Larebeke N. Endocrine-disrupting chemicals:
associated disorders and mechanisms of action. J Environ Public
Health. 2012;2012:713696. doi:10.1155/2012/713696.
206. Koch CA. EDITORIAL: BThe Koch’s^ view on the sense of taste
in endocrinology. Rev Endocr Metab Disord. 2016;17(2):143–7.
doi:10.1007/s11154-016-9383-y.
207. Brill MJ, Diepstraten J, van Rongen A, van Kralingen S, van
den Anker JN, Knibbe CA. Impact of obesity on drug metab-
olism and elimination in adults and children. Clin
Pharmacokinet. 2012;51(5):277–304. doi:10.2165/11599410-
000000000-00000.
208. James PA, Oparil S, Carter BL, Cushman WC, Dennison-
Himmelfarb C, Handler J, et al. evidence-based guideline for the
management of high blood pressure in adults: report from the
panel members appointed to the Eighth Joint National
Committee (JNC 8). JAMA. 2014;311(5):507–20. doi:10.1001
/jama.2013.284427.
209. McDonald E, Freedman DM, Alexander BH, Doody MM, Tucker
MA, Linet MS, et al. Prescription diuretic use and risk of basal cell
carcinoma in the nationwide U.S. radiologic technologists cohort.
Cancer Epidemiol Biomarkers Prev. 2014;23(8):1539–45.
doi:10.1158/1055-9965.EPI-14-0251.
210. Robinson SN, Zens MS, Perry AE, Spencer SK, Duell EJ, Karagas
MR. Photosensitizing agents and the risk of non-melanoma skin
cancer: a population-based case–control study. J Invest Dermatol.
2013;133(8):1950–5. doi:10.1038/jid.2013.33.
211. Kaae J, Boyd HA, Hansen AV, Wulf HC, Wohlfahrt J, Melbye M.
Photosensitizing medication use and risk of skin cancer. Cancer
Epidemiol Biomarkers Prev. 2010;19(11):2942–9. doi:10.1158
/1055-9965.EPI-10-0652.
212. Ruiter R, Visser LE, Eijgelsheim M, Rodenburg EM, Hofman A,
Coebergh JW, et al. High-ceiling diuretics are associated with an
increased risk of basal cell carcinoma in a population-based fol-
low-up study. Eur J Cancer. 2010;46(13):2467–72. doi:10.1016/j.
ejca.2010.04.024.
213. Glatz M, Hofbauer GF. Phototoxic and photoallergic cutaneous
drug reactions. Chem Immunol Allergy. 2012;97:167–79.
doi:10.1159/000335630.
214. Moore DE. Drug-induced cutaneous photosensitivity: incidence,
mechanism, prevention and management. Drug Saf. 2002;25(5):
345–72.
Rev Endocr Metab Disord (2016) 17:389–403
215. Stern RS. Photocarcinogenicity of drugs. Toxicol Lett. 1998;102–
103:389–92.
216. Stern RS, Bigby M. An expanded profile of cutaneous reactions to
nonsteroidal anti-inflammatory drugs. Reports to a specialty-based
system for spontaneous reporting of adverse reactions to drugs.
JAMA. 1984;252(11):1433–7.
217. Sanchez-Borges M, Capriles-Hulett A, Caballero-Fonseca F. Risk
of skin reactions when using ibuprofen-based medicines. Expert
Opin Drug Saf. 2005;4(5):837–48. doi:10.1517
/14740338.4.5.837.
218. Finch LE, Tomiyama AJ. Comfort eating, psychological stress,
and depressive symptoms in young adult women. Appetite.
2015;95:239–44. doi:10.1016/j.appet.2015.07.017.
219. Bliss SA, Warnock JK. Psychiatric medications: adverse cutane-
ous drug reactions. Clin Dermatol. 2013;31(1):101–9.
doi:10.1016/j.clindermatol.2011.11.014.
220. Borras L, Huguelet P. A case report of photosensitivity to
amisulpride. Prim Care Companion J Clin Psychiatry.
2007;9(2):153.
221. Warnock JK, Morris DW. Adverse cutaneous reactions to antipsy-
chotics. Am J Clin Dermatol. 2002;3(9):629–36.
222. Mennella JA, Bobowski NK, Reed DR. The development of sweet
taste: from biology to hedonics. Rev Endocr Metab Disord.
2016;17(2):171–8. doi:10.1007/s11154-016-9360-5.
223. Iwasaki JK, Srivastava D, Moy RL, Lin HJ, Kouba DJ. The mo-
lecular genetics underlying basal cell carcinoma pathogenesis and
links to targeted therapeutics. J Am Acad Dermatol. 2012;66(5):
e167–78. doi:10.1016/j.jaad.2010.06.054.
224. Bonilla X, Parmentier L, King B, Bezrukov F, Kaya G, Zoete V,
et al. Genomic analysis identifies new drivers and progression
pathways in skin basal cell carcinoma. Nat Genet. 2016;48(4):
398–406. doi:10.1038/ng.3525.
225. Rogers HW, Weinstock MA, Harris AR, Hinckley MR, Feldman
SR, Fleischer AB, et al. Incidence estimate of nonmelanoma skin
cancer in the United States, 2006. Arch Dermatol. 2010;146(3):
283–7. doi:10.1001/archdermatol.2010.19.
226. Makrantonaki EZC. Molecular mechanisms of skin aging: state of
the art. Acad Sci. 2007;1119:40–50.
227. Yan W, Wistuba II, Emmert-Buck MR, Erickson HS. Squamous
cell carcinoma—similarities and differences among anatomical
sites. Am J Cancer Res. 2011;1(3):275–300.
228. Ibiebele TI, van der Pols JC, Hughes MC, Marks GC, Williams
GM, Green AC. Dietary pattern in association with squamous cell
carcinoma of the skin: a prospective study. Am J Clin Nutr.
2007;85(5):1401–8.
229. Inoue T, Toda S, Narisawa Y, Sugihara H. Subcutaneous adipo-
cytes promote the differentiation of squamous cell carcinoma cell
403
line (DJM-1) in collagen gel matrix culture. J Invest Dermatol.
2001;117(2):244–50. doi:10.1046/j.0022-202x.2001.01431.x.
230. Rubin AI, Chen EH, Ratner D. Basal-cell carcinoma. N Engl J
Med. 2005;353(21):2262–9. doi:10.1056/NEJMra044151.
231. Marzuka AG, Book SE. Basal cell carcinoma: pathogenesis, epi-
demiology, clinical features, diagnosis, histopathology, and man-
agement. Yale J Biol Med. 2015;88(2):167–79.
232. Espinosa P, Pfeiffer RM, Garcia-Casado Z, Requena C, Landi MT,
Kumar R, et al. Risk factors for keratinocyte skin cancer in patients
diagnosed with melanoma, a large retrospective study. Eur J
Cancer. 2015;53:115–24. doi:10.1016/j.ejca.2015.10.058.
233. Reinau D, Surber C, Jick SS, Meier CR. Epidemiology of basal
cell carcinoma in the United Kingdom: incidence, lifestyle factors,
and comorbidities. Br J Cancer. 2014;111(1):203–6. doi:10.1038
/bjc.2014.265.
234. Baxter JM, Patel AN, Varma S. Facial basal cell carcinoma. BMJ.
2012;345, e5342. doi:10.1136/bmj.e5342.
235. Cheng P, Weng SD, Chiang CH, Lai FJ. Relationship between
arsenic-containing drinking water and skin cancers in the
arseniasis endemic areas in Taiwan. J Dermatol. 2016;43(2):
181–6.
236. Poschl G, Seitz HK. Alcohol and cancer. Alcohol Alcohol.
2004;39(3):155–65.
237. Saladi RN, Nektalova T, Fox JL. Induction of skin carcinogenicity
by alcohol and ultraviolet light. Clin Exp Dermatol. 2010;35(1):7–
11. doi:10.1111/j.1365-2230.2009.03465.x.
238. Song F, Qureshi AA, Gao X, Li T, Han J. Smoking and risk of skin
cancer: a prospective analysis and a meta-analysis. Int J
Epidemiol. 2012;41(6):1694–705. doi:10.1093/ije/dys146.
239. Leonardi-Bee J, Ellison T, Bath-Hextall F. Smoking and the risk of
nonmelanoma skin cancer: systematic review and meta-analysis.
Arch Dermatol. 2012;148(8):939–46. doi:10.1001
/archdermatol.2012.1374.
240. Hughes MC, Olsen CM, Williams GM, Green AC. A prospective
study of cigarette smoking and basal cell carcinoma. Arch
Dermatol Res. 2014;306(9):851–6. doi:10.1007/s00403-014-
1503-5.
241. Henderson MT, Kubo JT, Desai M, David SP, Tindle H, Sinha
AA, et al. Smoking behavior and association of melanoma and
nonmelanoma skin cancer in the Women’s Health Initiative. J Am
Acad Dermatol. 2015;72(1):190–1. doi:10.1016/j.
jaad.2014.09.024. e3.
242. Trost SG, Owen N, Bauman AE, Sallis JF, Brown W. Correlates of
adults’ participation in physical activity: review and update. Med
Sci Sports Exerc. 2002;34(12):1996–2001. doi:10.1249/01.
MSS.0000038974.76900.92.
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