Endocrine Abstracts

Duplication of the guanine nucleotide-binding protein beta subunit 3 (GNB3) gene is associated with early-onset obesity in individuals with an unbalanced chromosome translocation. Additionally, a cytosine to thymine (C825T) polymorphism in GNB3 is associated with hypertension, obesity and metabolic syndrome; however, the mechanism of GNB3-related obesity is unknown. We created BAC-transgenic mice that carry an extra copy of the human risk-allele (T) of GNB3.

Heterozygous mice express transgenic GNB3 in whole brain, hypothalamus, olfactory bulb, and cerebellum at levels significantly greater than endogenous Gnb3.

These GNB3-T mice weigh significantly more than their wild-type littermates starting at age 6–7 weeks (P=0.002). At 20 weeks, GNB3-T mice have increased adiposity, indicated by greater subcutaneous and visceral white adipose tissue (WAT) and brown adipose tissue (BAT) depots, larger white adipocytes, and larger livers compared to wild-types. Lean mass is approximately the same in GNB3-T and wild-type mice, suggesting that the difference in weight is strictly due to an increase in fat mass. GNB3-T mice have similar food intake and activity levels compared to wild-types. Fasting plasma ghrelin and PYY levels are similar to wild-types, while amylin is elevated in GNB3-T mice at 20 weeks, indicating proper satiety. GNB3-T mice have glucose intolerance and elevated fasting plasma glucose, insulin, C-peptide, consistent with type 2 diabetes. GNB3-T mice also have higher fasting plasma leptin, triglycerides, total cholesterol and phospholipids compared to wild-types. Volume oxygen consumed, heat produced and respiratory exchange ratio are not significantly different in GNB3-T mice and wild-types. GNB3-T mice have difficulty maintaining core body temperature during acute cold stress compared to wild-types. Citrate synthase activity in subcutaneous WAT and BAT depots is not different in GNB3-T and wild-types. GNB3-T mice have lower Ucp1 expression in subcutaneous WAT. Taken together, these data support a role for GNB3 overexpression in obesity and metabolic syndrome.