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

Frontiers in Endocrinology

Xianlin Han¹  Juan Pablo Palavicini¹  Meixia Pan¹  Ashish Singha³  Scotlynn Farmer³  Darleen Sandoval⁴  Teppei Fujikawa⁵ 

[1] Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, United States;Center for Biomedical Neuroscience, University of Texas Health San Antonio, San Antonio, TX, United States;Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, United States;Department of Surgery, University of Michigan, Ann Arbor, MI, United States;Division of Hypothalamic Research Center, Internal Medicine, UT Southwestern Medical Center at Dallas, Dallas, TX, United States;

关键词: leptin;    insulin deficiency;    the hypothalamus;    glucose metabolism;    lipid metabolism;   

DOI  :  10.3389/fendo.2020.588447

来源: DOAJ

【 摘 要 】

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-Cre25Mgn neurons) are required for central leptin signaling to reverse dyslipidemia, thereby hyperglycemia in insulin-deficient mice. Ablation of LEPRs in RIP-Cre25Mgn neurons completely blocks glucose-lowering effects of leptin in insulin-deficient mice. Further investigations reveal that insulin-deficient mice lacking LEPRs in RIP-Cre25Mgn neurons (RIP-CreΔLEPR 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-CreΔLEPR 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-CreΔLEPR mice, suggesting that excess circulating lipids are a driving-force of hyperglycemia in these mice. Collectively, our data demonstrate that LEPRs in RIP-Cre25Mgn neurons significantly contribute to glucose-lowering effects of leptin in an insulin-independent manner by improving dyslipidemia.

【 授权许可】

Unknown