Leptin Receptors in RIP-Cre^25Mgnneurons Mediate Anti-Dyslipidemia Effects of Leptin in Insulin-Deficient Male Mice

Abstract

Leptin is a potent endocrine hormone produced by adipose tissue and regulates a broad range of metabolism including glucose and lipid metabolism, with and without insulin. It is evident that central leptin signaling can lower hyperglycemia in insulin-deficient rodents via multiple mechanisms including restoration of dyslipidemia. However, the specific neurons that regulate these glucose-lowering and anti-dyslipidemia effects of leptin remain unidentified. Here we report that leptin receptors (LEPRs) in neurons expressing Cre recombinase driven by a short fragment of a promoter region of Ins2 gene (RIP-Cre 25Mgn neurons) are required for central leptin signaling to reverse hyperglycemia and dyslipidemia in insulin-deficient mice.Ablation of LEPRs in RIP-Cre 25Mgn neurons completely blocks glucose-lowering effects of leptin in insulindeficient mice. Further investigations reveal that insulin-deficient mice lacking LEPRs in RIP-Cre 25Mgn neurons (RIP-Cre ∆LEPR mice) exhibit greater lipid levels in blood and liver compared to wild-type controls, and that leptin injection into the brain does not suppress dyslipidemia in insulin-deficient RIP-Cre ∆LEPR mice. Leptin administration into the brain combined with acipimox, which lowers blood lipids by suppressing triglyceride lipase activity, can restore normal glycemia in insulin-deficient RIP-Cre ∆LEPR mice, suggesting that excess circulating lipids are a driving-force of hyperglycemia in insulin-deficient RIP-Cre ∆LEPR mice. Collectively, our data demonstrate that LEPRs in RIP-Cre 25Mgn neurons significantly contribute to glucose-lowering effects of leptin in an insulin-independent manner by suppression of dyslipidemia.

Leptin Receptors in RIP-Cre25Mgn Neurons Mediate Anti-dyslipidemia Effects of Leptin in Insulin-Deficient Mice

“…We would like to thank Nancy Gonzalez (UT Health San Antonio) for the technical assistant. This manuscript has been released as a pre-print at BioRxiv (69).…”

The leptin receptor has no role in delta-cell control of beta-cell function in the mouse

“…Two different models of Lepr deletion within beta cells have yielded conflicting results. Rat insulin promoter (RIPMgn)-Cre;Lepr mice display hyperglycemia and reduced insulin secretion, but they also have high adiposity due to RIP-CreMgn activity in the brain (10,11); therefore, the disrupted glucose homeostasis is likely a secondary Fig. 1.…”