Abstract
In a screen for genes that affect the metabolic response to high-fat diet (HFD), we selected one line of N-ethyl-N-nitrosourea (ENU)-mutagenized mice, Jll, with dominantly inherited resistance to diet-induced obesity (DIO). Mutant animals had dramatically reduced body weight and fat mass, and low basal insulin and glucose levels relative to unaffected controls. Both white adipose tissue (WAT) and brown adipose tissue (BAT) depots were smaller in mutant animals. Mutant animals fed a HFD gained only slightly more weight than animals fed regular chow, and were protected from hepatic lipid accumulation. The phenotype was genetically linked to a 5.7-Mb interval on chromosome 12, and sequencing of the entire interval identified a single coding mutation, predicted to cause a methionine-to-isoleucine substitution at position 279 of the Adcy3 protein (Adcy3M279I, henceforth referred to as Adcy3Jll). The mutant protein is hyperactive, possibly constitutively so, producing elevated levels of cyclic AMP in a cell-based assay. These mice demonstrate that increased Adcy3 activity robustly protect animals from diet-induced metabolic derangements.
Highlights
Obesity is both a national and worldwide epidemic
All animals were placed on high-fat diet (HFD) at 4 weeks of age and assessed for total body weight, fat mass, and insulin levels at 12 weeks of age
We have identified a dominant, gain-of-function point mutation in a component of the cAMP signaling pathway that promotes whole-body energy metabolism
Summary
Obesity is both a national and worldwide epidemic. The prevalence of obesity (body mass index (BMI) .30) is greater than 30% in the United States, and is even higher in some parts of the world with the highest prevalence in the Pacific Islands [1]. Single-gene mutations that cause obesity in mice or rats have long been known, establishing clearly that genetic mutations can cause obesity, and elucidating the pathways that control energy homeostasis [4]. In the case of prohormone convertase 1 (PC1), monogenic obesity was identified in humans before a corresponding, obesity-causing mutation was identified in mice [7,8] While these studies establish a genetic cause in rare, severe obesity, evidence for a genetic contribution to common obesity comes from adoption and twin studies, which show that 60–80% of variation in BMI is hereditary [9]. The genetic variants identified by GWAS so far, account for only a small percentage of the heritability in BMI [10]
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