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

Abstract

Leptin is a potent endocrine hormone produced by adipose tissue and regulates a broad range of whole-body metabolism such as glucose and lipid metabolism, even without insulin. Central leptin signaling can lower hyperglycemia in insulin-deficient rodents via multiple mechanisms, including improvements of dyslipidemia. However, the specific neurons that regulate 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 dyslipidemia, thereby hyperglycemia in insulin-deficient mice. Ablation of LEPRs in RIP-Cre 25Mgn neurons completely blocks glucose-lowering effects of leptin in insulin-deficient 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 these 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 improving dyslipidemia.

Central regulation of glucose metabolism in an insulin‐dependent and ‐independent manner

“…Insulin-deficient Gcgr-KO and Gcg-KO mice show longer survivability compared to insulin-deficient wild-type mice despite the fact that they are still hyperglycemic. 96,98 Overall, these studies indicate that hyperglucagonaemia has deleterious effects on longevity in insulin-deficient mice independently of its effects on glucose metabolism.…”

“…leptin. 98 These data suggest that LEPRs in RIP-Cre 25Mgn neurones are vital for leptin with respect to lowering blood lipids in insulin-deficient mice, and restoration of lipid metabolism is key for the glucose-lowering effects of leptin. RIP-Cre 25Mgn…”

“…97 Recently, we reported that knockout of the preproglucagon gene (Gcg) does not affect the glucose-lowering effects of leptin in insulin-deficient mice, implying that glucagon signalling itself is not required for these effects. 98 Collectively, these data indicate that reversing hyperglucagonaemia is not sufficient for leptin to restore normoglycaemia. However, these results do not mean that leptin's action on glucagon secretion does not contribute to anything.…”

“…leptin injection could not reverse hyperglycaemia in insulin-deficient RIP-Cre ∆LEPR mice. 98 Intracerebroventricular leptin administration also failed to reverse dyslipidaemia in insulin-deficient RIP-Cre ∆LEPR mice. Intriguingly, lowering circulating lipids by pharmacological lipolysis inhibitors reverse hyperglycaemia in insulin-deficient RIP-Cre ∆LEPR mice that have received i.c.v.…”

“…We have recently reported that RIP-Cre 25Mgn neurones, which express Cre recombinase driven by a short fragment of the Ins2 promoter region, contribute to the glucose-lowering effects of leptin in insulin-deficient mice. 98 A RIP-Cre 25Mgn line was generated for the purpose of targeting pancreatic β-cells. However, RIP-Cre 25Mgn mice express Cre recombinase in the CNS because (ⅰ) Ins2 mRNA is expressed in the CNS, although the levels are extremely low 133 and (ⅱ) transgenic mice-generation methods in the early era frequently leads to ectopic expression of the target gene in unexpected organs/cells populations.…”