Kisspeptin-10 Ameliorates Obesity-Diabetes with Diverse Effects on Ileal Enteroendocrine Cells and Pancreatic Islet Morphology in High-Fat Fed Female Mice

Kisspeptin is a neuropeptide recognised for a pivotal role within the reproductive system, but potentially important endocrine metabolic effects are less well understood. We examined effects of twice-daily intraperitoneal administration of saline vehicle or kisspeptin-10 (25 nmol/kg), for 21 days, on glucose homeostasis, energy balance, circulating hormones as well as the morphology-function of enteroendocrine and islet cells in high-fat diet (HFD) fed female mice, with normal diet (ND) mice as an additional control group. Kisspeptin-10 decreased body weight, blood glucose and energy intake to ND levels. HFD increased circulating follicle-stimulating hormone (FSH) levels, which were further enhanced by kisspeptin-10 along with luteinising hormone (LH) concentrations. Neither HFD nor kisspeptin-10 affected progesterone or corticosterone. In the ileum, kisspeptin-10 decreased crypt depth and restored villi length to ND control levels, as well as increasing the proportion of glucose-dependent insulinotropic polypeptide (GIP) positive cells when compared to HFD mice and glucagon-like peptide-1 (GLP-1) positive cells compared to ND mice. Peptide YY (PYY) immunoreactivity was unaltered by HFD or kisspeptin-10. Plasma GIP was unchanged but circulating GLP-1 and PYY were reduced to ND levels. Within the pancreas, total islet, beta- and alpha-cell areas were similar in all mice, but kisspeptin-10 intervention restored relative insulin area to ND levels. Glucagon radius, an indicator of peripherally located alpha-cells, was reduced in HFD mice but normalised by kisspeptin-10 alongside elevated glucagon-islet area. Notably, beta-cell proliferation was increased by kisspeptin-10 with no alteration in beta-cell apoptosis. Overall, we reveal a previously uncharacterised diverse metabolic role for kisspeptin in directly modulating the gut–pancreatic axis.