Contribution of the hypothalamus and gut to weight gain susceptibility and resistance in mice.

Abstract

Obesity susceptibility in humans and rodent strains varies in response to consumption of high-energy dense (HED) diets. However, the exact mechanism(s) involved in this susceptibility remain unresolved. Our aim was to gain greater insight by using C57BL/6J (B6) mice that separate into obesity-prone (DIO) and obesity-resistant (DR) groups following a HED diet for 6 weeks. Physiological, biochemical and gene expression assessment of energy balance were performed in DIO and DR mice on a HED diet and chow-fed mice. The increased weight gain of DIO compared to DR mice was associated with increased energy intake, plasma leptin and adiponectin levels but not reduced physical activity or resting energy expenditure. Hypothalamic POMC gene expression was elevated with no changes in NPY or AgRP expression. Adipose tissue leptin and adiponectin gene expression were significantly reduced in the DIO group compared to the DR group. Interestingly, ileum expression of G-protein-coupled receptor 40 (GPR40) was significantly increased whilst GPR120, GPR119, GPR41 and glucagon-like peptide 1 (GLP-1) were reduced. Contrastingly, the lower weight gain of DR was associated with elevated adipose tissue leptin and adiponectin gene expression but no differences in plasma hormone or hypothalamic gene expression levels relative to chow-fed mice. Therefore, our data demonstrate that susceptibility and resistance to diet-induced weight gain in the B6 mouse appears to be predominantly driven by peripheral rather than hypothalamic modifications with changes in gut-specific receptors a potentially important contributor to this diversity.