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Leptin reverses diabetes by suppression of the hypothalamic-pituitary-adrenal axis

Nature Medicine volume 20, pages 759–763 (2014)Cite this article

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Abstract

Leptin treatment reverses hyperglycemia in animal models of poorly controlled type 1 diabetes (T1D)1,2,3,4,5,6, spurring great interest in the possibility of treating patients with this hormone. The antidiabetic effect of leptin has been postulated to occur through suppression of glucagon production, suppression of glucagon responsiveness or both; however, there does not appear to be a direct effect of leptin on the pancreatic alpha cell7. Thus, the mechanisms responsible for the antidiabetic effect of leptin remain poorly understood. We quantified liver-specific rates of hepatic gluconeogenesis and substrate oxidation in conjunction with rates of whole-body acetate, glycerol and fatty acid turnover in three rat models of poorly controlled diabetes, including a model of diabetic ketoacidosis8. We show that the higher rates of hepatic gluconeogenesis in all these models could be attributed to hypoleptinemia-induced activity of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in higher rates of adipocyte lipolysis, hepatic conversion of glycerol to glucose through a substrate push mechanism and conversion of pyruvate to glucose through greater hepatic acetyl-CoA allosteric activation of pyruvate carboxylase flux. Notably, these effects could be dissociated from changes in plasma insulin and glucagon concentrations and hepatic gluconeogenic protein expression. All the altered systemic and hepatic metabolic fluxes could be mimicked by infusing rats with Intralipid or corticosterone and were corrected by leptin replacement. These data demonstrate a critical role for lipolysis and substrate delivery to the liver, secondary to hypoleptinemia and HPA axis activity, in promoting higher hepatic gluconeogenesis and hyperglycemia in poorly controlled diabetes.

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Figure 1: Leptin reverses hyperglycemia and excess gluconeogenesis from pyruvate and glycerol in rats with streptozotocin-induced T1D.
Figure 2: Lipid infusion for 24 h in rats fed a HFD for 3 d replicates the perturbations to fluxes seen in type 1 diabetics and hyperinsulinemic-diabetic rats and implicates increased substrate supply in the excess gluconeogenesis of T1D.
Figure 3: Substrate (Intralipid and heparin) infusion blocks the effect of leptin to suppress hepatic gluconeogenesis in rats with T1D.
Figure 4: Matching plasma corticosterone in 3-d HFD-fed corticosterone-infused rats to that of rats with T1D drives excess lipolysis, gluconeogenesis and hyperglycemia.

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Acknowledgements

We thank V. Samuel, D. Befroy and K. Petersen for helpful discussions and J. Dong, Y. Kosover, M. Kahn, B. Perler, J. Stack and M. Batsu for expert technical support. This study was funded by grants from the US National Institutes of Health (R01 DK-40936, R24 DK-085638, U24 DK-059635 and P30 DK-45735), an American Diabetes Association–Merck Clinical/Translational Science Postdoctoral Fellowship Award from the American Diabetes Association and the Novo Nordisk Foundation for Basic Metabolic Research.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA

    Rachel J Perry, Dongyan Zhang & Gerald I Shulman

  2. Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

    Rachel J Perry, Xian-Man Zhang, Naoki Kumashiro, Joao-Paulo G Camporez, Gary W Cline & Gerald I Shulman

  3. Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA

    Rachel J Perry & Gerald I Shulman

  4. Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA

    Douglas L Rothman

  5. Department of Biomedical Engineering, Yale University School of Medicine, New Haven, Connecticut, USA

    Douglas L Rothman

  6. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

    Gerald I Shulman

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Contributions

R.J.P. and G.I.S. designed the experimental protocols. R.J.P., X.-M.Z., D.Z., N.K., J.-P.G.C. and G.W.C. performed the studies. All authors contributed to the analysis of data. R.J.P. and G.I.S. wrote the manuscript.

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Correspondence to Gerald I Shulman.

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Supplementary Figures 1–9 and Supplementary Tables 1–2 (PDF 678 kb)

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Perry, R., Zhang, XM., Zhang, D. et al. Leptin reverses diabetes by suppression of the hypothalamic-pituitary-adrenal axis. Nat Med 20, 759–763 (2014). https://doi.org/10.1038/nm.3579

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