Molecular genetic aspects of weight regulation

Abstract

Background: Family and twin studies have empirically revealed a 40% to 70% heritability of body-mass index, yet only a few hereditary factors have been identified to date that increase the risk of being overweight.

Methods: We present the current state of molecular genetic research on obesity with a selective review of the literature.

Results: A number of monogenic recessive mutations causing obesity have been identified, but these are rare. Various dominant mutations of the melanocortin-4 receptor gene are found in about 1% to 4% of all markedly obese persons. Current molecular genetic research focuses on the identification of common DNA variants affecting body weight; the genetic material of hundreds of thousands of people from around the world has now been investigated in genome-wide association studies. More than 30 variants conferring an increased risk have been identified, most of which are single nucleotide polymorphisms (SNPs) of no immediately clear functional significance. On average, these variants raise body weight by 500 g (range, 180 to 1400 g). Aside from SNPs, variations in the number of copies of specific DNA sequences have also been linked to obesity, as well as to subnormal weight. All the hereditary factors that have been identified to date account for about 5% of the variability of BMI. Extrapolation yields figures ranging from 10% to 15%.

Conclusions: The amount of genetic variability seen to date at the DNA level accounts only for a small fraction of the inter-individual variability of BMI. Obesity is thought to be a largely hereditary condition; the fact that its genetic basis has not yet been demonstrated may be due to various genetic or experimental factors.

Figure 1

Leptin is generated in adipose tissue and transported via the bloodstream to the hypothalamus. The binding of leptin to leptin receptors (ObRb) stimulates the expression of cocaine- and amphetamine-regulated transcript (CART) and pro-opiomelanocortin (POMC). Simultaneously the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP) is suppressed. POMC is transformed by means of proprotein convertase 1 (coded by PCSK1), partly into α-melanocyte-stimulating hormone (α-MSH), which functions as an agonist of the melanocortin-4 receptor (MC4R). The stimulation of MC4R, or the resulting activation of brain-derived neurotrophic factor (BDNF), which binds to tyrosine kinase receptor B (TrkB), leads to a saturated (anorexigenic) state. If, in contrast, little or no leptin is present, the hunger-stimulating (orexigenic) peptides NPY and AgRP are expressed. AgRP is a direct antagonist of MC4R. A large proportion of the mutations that lead to monogenic forms of obesity are found in the genes that code for the proteins of the leptinergic–melanocortinergic metabolic pathway (red boxes). For three of these genes (POMC, MC4R, and BDNF), genome-wide significant single nucleotide polymorphisms (SNPs) that contribute to polygenic forms of obesity were found in genome-wide association studies (GWAS).

Figure 2

Effect estimators of genetic variants for body weight identified by meta-analysis of genome-wide association studies

Figure 3

Combined estimated additive effect of the risk alleles that predispose to overweight on weight increase in a 180-cm-tall adult male from the European population (modified from Speliotes et al. 2010 [21])