Unaltered hypothalamic metabolic gene expression in Kiss1r KO mice despite obesity and reduced energy expenditure

Abstract

Kisspeptin controls reproduction by stimulating GnRH neurons via its receptor Kiss1r. Kiss1r is also expressed other brain areas and in peripheral tissues, suggesting additional non-reproductive roles. We recently determined that Kiss1r knockout (KO) mice develop an obese and diabetic phenotype. Here, we investigated whether Kiss1r KOs develop this metabolic phenotype due to alterations in the expression of metabolic genes involved in the appetite regulating system of the hypothalamus, including neuropeptide Y (Npy) and pro-opiomelanocortin (Pomc), as well as leptin receptor (Lepr), ghrelin receptor (Ghsr), and melanocortin receptor 3 and 4 (Mc3r, Mc4r). Body weights, leptin levels, and hypothalamic gene expression were measured in both gonad-intact and gonadectomised (GNX) mice at 8 and 20 weeks of age, fed either normal chow or a high-fat diet. We detected significant increases in Pomc expression in gonad-intact Kiss1r KOs at 8 weeks and 20 weeks, but no alterations in the other metabolic-related genes. However, the Pomc increases appeared to reflect genotype differences in circulating sex steroids, because GNX wildtype (WT) and Kiss1r KOs exhibited similar Pomc levels, along with similar Npy levels. The altered Pomc gene expression in gonad-intact Kiss1r KOs is consistent with previous reports of reduced food intake in these mice and may serve to increase the anorexigenic drive, perhaps compensating for the obese state. However, the surprising overall lack of changes in any of the hypothalamic metabolic genes in GNX KOs suggests that the aetiology of obesity in the absence of kisspeptin signalling may reflect peripheral rather than central metabolic impairments.

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