A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance.

The melanocortin-4 receptor (MC4R) plays a critical role in the control of energy balance. Of its two pro-opiomelanocortin (POMC)-derived ligands, alpha- and beta-MSH, the majority of attention has focused on alpha-MSH, partly reflecting the absence of beta-MSH in rodents. We screened the POMC gene in 538 patients with severe, early-onset obesity and identified five unrelated probands who were heterozygous for a rare missense variant in the region encoding beta-MSH, Tyr221Cys. This frequency was significantly increased (p < 0.001) compared to the general UK Caucasian population and the variant cosegregated with obesity/overweight in affected family members. Compared to wild-type beta-MSH, the variant peptide was impaired in its ability to bind to and activate signaling from the MC4R. Obese children carrying the Tyr221Cys variant were hyperphagic and showed increased linear growth, both of which are features of MC4R deficiency. These studies support a role for beta-MSH in the control of human energy homeostasis.

Studies of the peptide YY and neuropeptide Y2 receptor genes in relation to human obesity and obesity-related traits.

Peptide-YY (PYY) is secreted from endocrine L-cells of the gastrointestinal tract in response to caloric ingestion and may mediate postprandial satiety through the hypothalamic neuropeptide Y2 receptor (Y2R). We examined whether variants in the genes encoding PYY and Y2R might be associated with obesity-related phenotypes in humans. Among 101 subjects with severe early-onset obesity and a history of hyperphagia, we found two rare sequence variants-L73P and IVS2 + 32delG-in PYY and three rare missense mutations-L40F, F87I, and A172T-in Y2R. Although none of these were found in 100 normal-weight white control subjects, L73P in PYY and F87I and A172T in Y2R did not segregate with obesity in family studies, and family data were unavailable for IVS2 + 32delG in PYY and L40F in Y2R. Two common single nucleotide polymorphisms (SNPs), R72T and IVS3 + 68C>T, in PYY were in tight linkage disequilibrium but showed no association with BMI in a large white population. In the Y2R, two SNPs, 585T>C and 936T>C, were found and were in tight linkage disequilibrium. Men, homozygous for the rarer variant, had significantly lower BMI (P = 0.017), waist-to-hip ratio (P = 0.013), and, surprisingly, higher nonesterified fatty acid levels (P = 0.01). In conclusion, mutations in PYY and Y2R are not commonly found in humans with severe early-onset obesity. The relationship between common variants in Y2R and obesity-related traits deserves further exploration in other populations.

Contribution of variants in the small heterodimer partner gene to birthweight, adiposity, and insulin levels: mutational analysis and association studies in multiple populations.

Loss of function mutations in the small heterodimer partner (SHP) gene have been reported to cause obesity and increased birth weight. We examined the relation between genetic variation in SHP and birth weight, adiposity, and insulin levels in three independent populations. The coding regions and 562 bases of the SHP promoter were screened for mutations in 329 subjects with severe early-onset obesity. Two novel missense mutations, R34G and R36C, were identified; these were not found in control subjects and did not cosegregate with obesity in family studies. Two common polymorphisms, G171A and -195CTGAdel, were found in 12 and 16% of subjects, respectively. Within the obese cohort, G171A and -195CTGAdel carriers had higher and lower birth weights, respectively, than wild-type subjects, the rare homozygotes for G171A being particularly large at birth. In a U.K. population-based cohort of 1,079 children, the 171A allele was associated with higher BMI (P < 0.05) and waist circumference (P = 0.001). Children carrying the G171A variant had higher 30-min insulin responses to a glucose load (P = 0.03). In conclusion, although mutations in SHP are not a common cause of severe human obesity, genetic variation in the SHP locus may influence birth weight and have effects on BMI, possibly through effects on insulin secretion.