Obesity rates are rapidly increasing worldwide and facilitate the development of many related disease states, such as cardiovascular disease, the metabolic syndrome, type 2 diabetes mellitus, and various types of cancer. Variation in metabolically important genes can have a great impact on a population's susceptibility to becoming obese and/or developing related complications. The adipokines adiponectin and leptin, as well as the leptin receptor, are major players in the regulation of body energy homeostasis and fat storage. This paper summarizes the findings of single nucleotide polymorphisms in these three genes and their effect on obesity and metabolic disease risk. Additionally, studies of gene-nutrient interactions involving adiponectin, leptin, and the leptin receptor are highlighted to emphasize the critical role of diet in susceptible populations.
Obesity is the result of an imbalance in energy homeostasis and is characterized by increased adipose tissue mass, chronic low-grade inflammation, insulin resistance, and endothelial dysfunction. Obesity is a major risk factor for type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and several types of cancer [
Adipose tissue plays multiple important roles in body weight regulation and energy homeostasis. Adipose functions as an energy storage organ, storing fat primarily in the form of triglycerides and releasing free fatty acids as the body’s energy demands change. Adipose tissue is also an active endocrine organ, secreting many cytokines, chemokines, and hormone-like factors. These molecules, which are produced and secreted primarily by adipocytes, are known as adipokines [
Since many critical metabolic functions are influenced by adipokines, genetic variations that affect their efficacy may contribute to various pathophysiological states. For instance, genetic variation in adipokine genes has been shown to modulate circulating adipokine levels and thus could predispose carriers of single nucleotide polymorphisms (SNPs) to developing obesity or other metabolic illnesses in which adipokines play a prominent role, or alternatively, provide them some protection against disease. Studying the impact of such gene polymorphisms in human populations can provide insight into the roles specific adipokines play in obesity and related pathologies. This paper will discuss the association of SNPs in the protein-coding genes for two well-studied adipokines, adiponectin and leptin, as well as the leptin receptor, in the context of obesity-related metabolic disease. In addition, due to the profound effect that diet can have on weight gain and regulation, the recent literature on nutrient-gene interaction studies involving adipokines and dietary factors will be highlighted.
Articles for this review were identified using the PubMed/Medline databases. Search terms included “single gene polymorphism”, “gene variant”, “adiponectin”, “AdipoQ”, “leptin”, “leptin receptor”, and “obesity” or “metabolic disease”. An emphasis was placed on studies published in the last decade, but the search was not limited to a specific time interval. The articles were chosen by scanning the abstract to ensure relevancy. Only studies in human populations and in English were included.
Adiponectin is an important anti-inflammatory and insulin-sensitizing hormone and promotes lipid oxidation in tissues such as skeletal muscle and liver [
It is estimated that a 30–70% variation in normal circulating adiponectin levels can be attributed to genetic factors [
SNPs in the adiponectin gene
SNP ID | Position | Parameter association | Population | Adiponectin level | Reference | |
---|---|---|---|---|---|---|
rs860291 | −12823 | No association with T2DM, BMI, or insulin sensitivity | Pima Indians | [ | ||
rs16861194 | −11426 | SNP associated with increased risk for gaining weight in diabetics | Chinese (T2DM) | [ | ||
SNP associated with fasting plasma glucose in T2DM patients and in those with impaired glucose tolerance | Swedish Caucasians (T2DM/ impaired glucose tolerance/ nondiabetic) | [ | ||||
G allele moderately associated with T2DM | French Caucasians | [ | ||||
rs17300539 | −1391 | A allele associated with higher adn levels, higher BMI, and obesity | Children of European origin | 13.39 | 6.00 | [ |
A allele carriers have lower weight, waist and hip circumferences and BMI | [ | |||||
GA carriers had increased risk for becoming hyperglycaemic/diabetic | French Caucasians | [ | ||||
A allele associated with higher adn levels | French Caucasians | .0001 | [ | |||
A allele associated with higher adn levels | Hispanic Americans and African Americans | 18.89 | .0001 | [ | ||
A allele associated with higher adn levels | Caucasians | [ | ||||
A allele associated with higher adn levels | Caucasian women | 36.93 | .0006 | [ | ||
A allele associated with higher adn levels in obese children | French Caucasians (obese/lean) | .005 | [ | |||
A allele associated with higher adn | Caucasian and African American adolescents | 29.41 | .002 | [ | ||
A allele associated with higher adn levels | Caucasians | 19.05 | .0005 | [ | ||
A associated with lower adn levels, lower insulin sensitivity, and higher risk of T2DM in obese subjects | French Caucasians (lean/obese) | 32.01 | .0003 | [ | ||
rs266729 | −11377 | C allele associated with higher fasting plasma glucose levels in diabetics | Chinese (T2DM) | [ | ||
C allele associated with severe obesity | French Caucasians (obese/lean) | [ | ||||
G allele associated with lower adn levels, higher risk of hypertension | Chinese (hypertensive) | .0037 | [ | |||
SNP associated with increase in plasma oxidative stress markers | T2DM patients | [ | ||||
G allele associated with lower adn levels, lower insulin sensitivity, and higher risk of T2DM in obese subjects | French Caucasians (lean/obese) | 20.66 | .008 | [ | ||
G allele associated with coronary stenoses and lower adn levels | European men with CVD | 26.92 | .003 | [ | ||
SNP associated with increased risk for colorectal cancer | Czech patients | [ | ||||
No association with adn levels | Caucasian Italians | [ | ||||
No association with colorectal cancer risk | UK | [ | ||||
GG and CG associated with lower CRC risk | American CRC patients | [ | ||||
G associated with lower adn levels | French Caucasians | .0003 | [ | |||
CC and CG genotypes had higher BMI than GG | Swedish Caucasians (T2DM/ impaired glucose tolerance/ nondiabetic) | [ | ||||
−11365 | SNP associated with lower plasma adn levels | 18.36 | .007 | [ | ||
No association with T2DM, BMI, or insulin sensitivity | Pima Indians | [ | ||||
−10677 | SNP associated with lower adn levels | Chinese (hypertensive) | .0027 | [ | ||
rs182052 | −10068 | A allele associated with lower adn levels | Hypertensive Chinese | .0001 | [ | |
A allele associated with waist circumference | American Caucasian young adults | [ | ||||
G allele associated with higher adn | Caucasian and African American adolescents | 17.58 | 0.03 | [ | ||
−10066 | G allele associated with higher adn | Caucasian women | 8.67 | .01 | [ | |
rs16861209 | −7734 C > A | A allele associated with higher adn | Caucasian women | 22.68 | .004 | [ |
rs822395 | −4041 A > C | No association with adn levels | Caucasian Italians | [ | ||
−4034 | CC associated with CVD risk | [ | ||||
−3971 G > A | A allele associated with worse glucose tolerance and insulin sensitivity, but not adn levels | Caucasian Canadians (nondiabetic) | [ | |||
rs2241766 | +45 T > G | GG and TG genotypes were at higher risk for T2DM | Obese Iranians | [ | ||
Both TG and GG genotypes were associated with gestational T2DM, whereas among healthy participants, the TT genotype had higher adn levels than other groups | Pregnant (<18 weeks) Malaysian women | 19.92 | .05 | [ | ||
G allele associated with lower fasting insulin levels and lower HOMA-IR score | Nondiabetic Greek women | [ | ||||
G allele associated with higher TG, HOMA, fasting blood glucose, BMI and ALT, and lower adn levels; T allele associated with lower body weight | Chinese (NAFLD/metabolic syndrome) | 28.68 | .008 | [ | ||
GG associated with T2DM | Japanese | [ | ||||
G allele associated with T2DM (lower insulin sensitivity), lower adn, higher blood pressure, higher LDL and total cholesterol levels | Chinese (T2DM) | 15.47 | .01 | [ | ||
A allele associated with worse glucose tolerance and insulin sensitivity, but not adn levels | Caucasian Canadians (nondiabetic) | [ | ||||
G allele associated with BMI and waist circumference | Hispanic Americans | [ | ||||
GG carriers had higher risk of becoming hyperglycaemic/diabetic, associated with increase in BMI and WHR over 3 years | French Caucasian | [ | ||||
No difference in risk for T2DM or IR | Korean (diabetic/ nondiabetic) | [ | ||||
T allele and TG genotype associated with lower serum adn, no association with IR | Caucasians | 25.17 | .0008 | [ | ||
GT genotype associated with impaired glucose tolerance | Spanish | [ | ||||
G allele conferred higher risk of developing T2DM than TT genotype, particularly when combined with SNP +276 T allele | European/Canadian subjects with impaired glucose tolerance | [ | ||||
T allele associated with lower BMI and HOMA-IR | Japanese (nondiabetic) | [ | ||||
In obese subjects, serum cholesterol and waist circumference were lower in TG genotype than in TT genotype | Swedish women (obese/lean) | [ | ||||
No association with adn levels | Caucasian Italians | [ | ||||
No association with risk for coronary artery disease | Caucasian Italians (T2DM) | [ | ||||
No association with T2DM, BMI, or insulin sensitivity | Pima Indians | [ | ||||
G allele associated with coronary artery disease in T2DM patients | European Caucasians | [ | ||||
G associated with higher adn levels | French Caucasians | .01 | [ | |||
rs1501299 | +276 G > T | T allele associated with obesity | African American men | [ | ||
GG associated with T2DM, higher insulin resistance, and lower adn levels in subjects with higher BMI | Japanese | 10.40 | .01 | [ | ||
T allele associated with higher adn levels | Caucasian women | 4.46 | .0031 | [ | ||
T allele associated with central obesity and hyperglycemia | Indigenous Taiwanese | [ | ||||
T allele associated with lower adn levels, diastolic blood pressure | Finnish men | 33.58 | .001 | [ | ||
T allele associated with higher fasting insulin levels and higher HOMA-IR score, possible association with body fat | Greek women (nondiabetic) | [ | ||||
GG genotype associated with lower adn levels, impaired glucose tolerance | Spanish | .015 | [ | |||
SNP associated with higher rate of insulin resistance, higher n-6/n-3 LCPUFA ratio in plasma phospholipids | Normolipidaemic obese children | [ | ||||
T allele associated with severe obesity, but not adn | French Caucasians (obese/lean) | [ | ||||
TT genotype associated with lower CVD risk in diabetic patients, those without CVD had higher adn levels | American men (T2DM) | 27.03 | .0029 | [ | ||
T allele is an important determinant of CAD and lower adn levels in patients with early onset CAD (50 years of age or less) | Italian CAD patients | [ | ||||
T allele associated with higher adn | Caucasian and African American adolescents | 4.95, 5.81 | .05,.03 | [ | ||
G allele carriers had higher TG, higher small dense LDL, and smaller LDL particle size; GG had lower adn, higher HOMA-IR | Korean (nondiabetic) | 18.90 | .026 | [ | ||
No association with adn levels or hypertension | Japanese men (hypertensive/ normotensive) | [ | ||||
No difference in allele frequencies between diabetic and nondiabetic, no difference in risk of T2DM or insulin resistance | Korean (diabetic/ nondiabetic) | [ | ||||
No association with T2DM, BMI, or insulin sensitivity | Pima Indians | [ | ||||
TT genotype associated with lower risk of coronary artery disease in T2DM patients | Caucasian Italians (T2DM) | [ | ||||
TT genotype associated with higher adn levels | Caucasian Italians | .032 | [ | |||
G allele, GT genotype associated with lower serum adn, no association with insulin resistance | Caucasians | 13.70 | .00005 | [ | ||
T allele associated with lower BMI and HOMA-IR | Japanese (nondiabetic) | [ | ||||
T associated with higher adn levels | French Caucasians | .01 | [ | |||
rs1063538 | +3228 C > T | T allele associated with higher adn levels | Caucasian women | 24.97 | .036 | [ |
rs1063538 | +3286 | No association with T2DM, BMI, or insulin sensitivity | Pima Indians | [ | ||
+10211 T > G | G allele associated with higher diabetes risk, higher BMI, and lower adn levels | Asian Indians | .007 | [ | ||
rs12495941 | G > T | T allele associated with lower adn levels | Chinese (hypertensive) | .0001 | [ | |
rs3774261 | A > G | G allele associated with IR | African Americans | [ | ||
rs1656943 (rs822387) | T > C | C allele associated with higher adn levels | Hispanic Americans and African Americans | 12.62 | .003 | [ |
The majority of studies analyzing the SNP −11391 G > A found a favourable increase in circulating adiponectin levels in those subjects carrying the A allele. A recent meta-analysis determined that SNP −11391 G>A was associated with adiponectin levels according to a dominant model with A allele carriers (GA and AA genotypes) having higher adiponectin levels compared with GG carriers [
The findings on the −11377 G > C SNP are inconsistent, but the general trend links the G allele to various detrimental conditions, including lower adiponectin levels [
The silent +45 T > G SNP is strongly associated with detrimental health effects including lower adiponectin levels [
The G allele of the +276 G > T SNP is primarily associated with lower insulin sensitivity and increased T2DM risk, lower adiponectin levels, and increased blood lipids. Conversely, many carriers of the T allele have higher adiponectin levels and a lower BMI. Two notable exceptions to this trend are the studies authored by Beebe-Dimmer et al. [
Overall, the magnitude of change in adiponectin levels varies considerably between studies. This is not surprising, since the studies examine populations that are very different in ethnicity, age, and health condition. However, it is worth noting that several studies show quite substantial changes in adiponectin levels and therefore provide convincing evidence that seemingly minute variations in the genetic code can produce large changes in adipokine levels, and thus significantly affect health status.
Subtle genetic variations can have a large impact on important obesity-related disease determinants, as demonstrated by many of studies discussed above. Individuals with SNPs in genes such as
Leptin regulates body weight and energy expenditure, and plays important roles in the modulation of glucose and lipid metabolism, angiogenesis, immunity, and blood pressure homeostasis. Leptin is also a critical signalling molecule in the hypothalamus, where it influences appetite and satiety. The circulating levels of leptin correlate directly with adipocyte number and size [
The study of leptin began when mice homozygous for single-gene mutations in the leptin gene (
SNPs in the Leptin (
SNP ID | Amino acid change | Nucleotide change | Parameter association | Population | Leptin level (% change) | Reference | |
---|---|---|---|---|---|---|---|
Leptin ( | |||||||
rs4731427 | SNP associated with weight and waist circumference in African Americans | Young adults (Caucasians, African Americans) | [ | ||||
+19G > A | No association with BMI, WHR, fasting glucose & insulin, lipids and leptin levels | [ | |||||
No association with waist girth, plasma triglycerides, HDL-cholesterol, glucose and systolic, and diastolic blood pressure | French Caucasian | [ | |||||
No association with waist-to-hip ratio, fasting leptin, total cholesterol, high-density lipoproteins, triglycerides | Italian Caucasian (obese/non-obese) | [ | |||||
No genotype associated with BMI, but A allele associated with higher leptin levels in obese patients | French Caucasian (obese/non-obese) | 18.93 | .001 | [ | |||
A allele in females associated with lower body weight, BMI and plasma leptin levels, lower risk of obesity | African Americans and Caucasians | 6.68 | .01 | [ | |||
rs17151919 | SNP associated with weight and waist circumference in African Americans and weight in Caucasians, waist circumference in Caucasian women | Young adults (Caucasians, African Americans) | [ | ||||
rs28954369 | SNP associated with weight, waist circumference in African Americans and weight in Caucasians, waist circumference in Caucasian women | Young adults (Caucasians, African Americans) | [ | ||||
rs2167270 | SNP associated with weight in Caucasians, waist circumference in Caucasian women | Young adults (Caucasians, African Americans) | [ | ||||
rs7799039 | G > A | A allele significantly associated with BMI | Caucasians | [ | |||
−2548 G > A | G allele associated with overweight, and with lower leptin concentrations in men | 17.46 | .05 | [ | |||
A allele not associated with obesity | Spanish Mediterranean | [ | |||||
Leptin Receptor ( | |||||||
rs1137101 | Gln223Arg | A > G | G allele associated with BMI, WHR, leptin levels, and insulin levels | Asian Indians (diabetic/ nondiabetic) | .001 | [ | |
G allele associated with higher BMI, fat mass, and serum leptin levels | Caucasian women (post-menopausal) | 31.15 | .0001 | [ | |||
GG genotype associated with BMI in nonsmokers | Brazilians of European descent (Caucasian) | [ | |||||
G allele associated with increased rates of obesity, higher BMI and % fat mass | Greek | [ | |||||
GG genotype had larger subcutaneous abdominal adipocyte size than AA, however, no difference in overall adiposity | Pima Indians | [ | |||||
G allele associated with insulin resistance | Caucasians | [ | |||||
GG phenotype associated with lean phenotype | Spanish Mediterranean | [ | |||||
GG and AG genotypes associated with increased risk of familial hypercholesterolemia, but not obesity, insulin resistance or other lipid parameters | Dutch | [ | |||||
G allele associated with increased rate of obesity | Brazilians (obese/non-obese) | [ | |||||
AA genotype was associated with increased total abdominal fat | Belgian Caucasian women (overweight and obese) | [ | |||||
No association with BMI, fasting insulin, HOMA-IR, serum leptin, or soluble leptin receptor levels | Japanese | [ | |||||
G allele associated with increased adiposity | Danish postmenopausal women | [ | |||||
GG genotype had lower blood pressure compared to AA | Swedish men (hypertensive/ normotensive) | [ | |||||
G allele associated with CRC risk | Czech (CRC patients) | [ | |||||
G allele associated with higher fat mass and BMI | [ | ||||||
A allele associated with higher insulin, leptin levels, and body fat | Mexican adolescents | 62.02 | .001 | [ | |||
No association with BMI, WHR, fasting glucose & insulin, lipids and leptin levels | [ | ||||||
AA genotype had greater risk of developing T2DM | Finnish (impaired glucose tolerance) | [ | |||||
G allele associated with BMI, change in BMI over time | [ | ||||||
Ser(T)343-Ser(C) | T > C | T allele associated with overweight and fat mass in women; C allele carriers more responsive to weight loss on a low calorie diet | [ | ||||
+70 T > C | C allele associated with fat mass in women | [ | |||||
Lys656Asn | G>C | G allele associated with higher lean and fat mass | Caucasians | [ | |||
No association with obesity, BMI, or % fat mass | Greek | [ | |||||
C allele associated with increased hip circumference, total abdominal fat, and subcutaneous fat | Belgian Caucasian women (overweight and obese) | [ | |||||
C allele associated with higher fasting glucose and fasting insulin in postmenopausal women | Belgian Caucasian women (overweight and obese) | [ | |||||
No association with blood pressure or BMI | Swedish men (hypertensive/ normotensive) | [ | |||||
No association with blood pressure, serum glucose, insulin, or leptin levels | Mexican adolescents | [ | |||||
Arg109Lys | +5193 G > A | No association with BMI, WHR, fasting glucose & insulin, lipids and leptin levels | [ | ||||
AA genotype was associated with higher leptin levels in postmenopausal women | Belgian Caucasian women (overweight and obese) | 14.99 | .02 | [ | |||
A allele positively associated with BMI | Korean | [ | |||||
No association with BMI, fasting insulin, HOMA-IR, serum leptin, or soluble leptin receptor levels | Japanese | [ | |||||
No association with obesity, BMI, or % fat mass | Greek | [ | |||||
A allele associated with fasting insulin in postmenopausal women | Belgian Caucasian women (overweight and obese) | [ | |||||
AA genotype had greater risk of developing T2DM | Finnish (impaired glucose tolerance) | [ | |||||
GG genotype had lower blood pressure and lower BMI compared to AA | Swedish men (hypertensive/ normotensive) | [ | |||||
rs1045895 | SNP associated with change in BMI over time | [ |
The
The
The Lys656Asn G > C SNP was analyzed in several different populations, but no consistent trends were identified—both alleles are associated with increased fat mass in different ethnic groups [
The A allele of the Arg109Lys G > A SNP is associated with increased T2DM risk [
Functional data on these polymorphisms is scarce, and the mechanisms by which the genetic variation influences metabolism and obesity are largely speculative at this point in time. The increased fat mass and leptin levels in many of the
Most of the literature on gene-nutrient interactions involving leptin or the leptin receptor focuses on fetal nutrition and leptin levels in breast-feeding mothers. Recent evidence suggests that early prenatal and postnatal nutrition has an impact on susceptibility to chronic disease later in life. Leptin in breast milk has been identified as a key protective factor against several metabolic and physiological changes at an older age, such as obesity and related medical complications [
There is scant research on the interactions of leptin or leptin receptor gene SNPs with dietary factors. One study analyzed the effects of leptin receptor polymorphisms and PUFA consumption in relation to insulin resistance and metabolic syndrome [
In summary, the current literature demonstrates that SNPs in the genes for adiponectin, leptin, and the leptin receptor can to a great degree influence the carriers’ susceptibility to obesity and related complications. While epidemiological studies have reported associations between adipokine levels and metabolic disease parameters, the evidence compiled here provides a compelling argument for the causality of adipokine levels in disease. In many of the studies cited here, changes in adipokine levels were observed in individuals with gene polymorphisms, and thus, the change in adipokine levels precedes the occurrence of pathological conditions. Varied downstream effects on parameters of health are to be expected, since the adipokines examined here play diverse roles in many organ systems, as recently reviewed by DeClercq et al. [
Adiponectin
Body mass index
Coronary artery disease
Colorectal cancer
Cardiovascular disease
Fasting serum insulin
Homeostatic model assessment of insulin resistance
Insulin resistance
Long chain polyunsaturated fatty acid
Low density lipoprotein
Monounsaturated fatty acid
Polyunsaturated fatty acid
Single nucleotide polymorphism
Type 2 diabetes mellitus
Waist-to-hip ratio.
This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada.