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

Journal name:
Nature Medicine
Volume:
20,
Pages:
759–763
Year published:
DOI:
doi:10.1038/nm.3579
Received
Accepted
Published online

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.

At a glance

Figures

  1. Leptin reverses hyperglycemia and excess gluconeogenesis from pyruvate and glycerol in rats with streptozotocin-induced T1D.
    Figure 1: Leptin reverses hyperglycemia and excess gluconeogenesis from pyruvate and glycerol in rats with streptozotocin-induced T1D.

    (a) Fasting plasma glucose concentrations in control nondiabetic rats, rats with T1D and rats with T1D treated with leptin (T1D-leptin). n = 8 controls, n = 6 T1D, n = 8 T1D-leptin. (b) Fasting plasma insulin concentrations. n = 7 controls, n = 7 T1D, n = 6 T1D-leptin. (c) Fasting plasma glucagon concentrations. n = 7 controls, n = 6 T1D, n = 16 T1D treated with leptin for 6 h, n = 5 T1D treated with leptin for 24 h. (d) Fasting plasma leptin concentrations. n = 8 for all groups. (e) Hepatic gluconeogenesis from pyruvate (lower bars) and glycerol (upper bars). The P values over the bars are from comparisons of total gluconeogenic flux. In eh, n = 6 for all groups. (fh) Whole-body glycerol, fatty acid (palmitate) and acetate turnover. (i) Liver acetyl-CoA concentrations. n = 12 controls, n = 6 T1D, n = 6 T1D-leptin. (j) Plasma corticosterone concentrations measured at 12:00 p.m. n = 7 controls, n = 8 T1D, n = 6 T1D-leptin. Throughout the figure, the data are shown as the mean ± s.e.m. *P < 0.05, ***P < 0.001, ****P < 0.0001 compared to control; ##P < 0.01, ###P < 0.001, ####P < 0.0001 compared to T1D; §§§P < 0.001 compared to T1D-leptin 6 h. NS, not significant. Throughout the figure, all groups were compared using analysis of variance (ANOVA) with Bonferroni correction.

  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 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.

    (a) Plasma glucose concentrations in high fat–fed nondiabetic untreated rats and rats fed a HFD and infused with heparin and Intralipid (HFD-lipid). (b) Hepatic gluconeogenesis from pyruvate (lower bars) and glycerol (upper bars). (c) TCA cycle flux from fatty acid oxidation (lower bars) and through PDH (upper bars). (d,e) Whole-body glycerol and fatty acid (palmitate) turnover. (f) Liver acetyl-CoA concentrations. Throughout the figure, the data are shown as the mean ± s.e.m. of n = 6 per group. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Statistical analyses were performed using two-tailed unpaired Student's t test. Asterisks under the lower bars represent comparisons of gluconeogenesis from pyruvate, asterisks over the upper bars represent comparisons of gluconeogenesis from glycerol and the uppermost asterisks represent comparisons with total gluconeogenesis.

  3. Substrate (Intralipid and heparin) infusion blocks the effect of leptin to suppress hepatic gluconeogenesis in rats with T1D.
    Figure 3: Substrate (Intralipid and heparin) infusion blocks the effect of leptin to suppress hepatic gluconeogenesis in rats with T1D.

    (a) Fasting plasma glucose in rats with T1D treated with leptin or treated with leptin and infused with lipids (T1D-leptin-lipid). (b) Hepatic gluconeogenesis from pyruvate (lower bars) and glycerol (upper bars). (c) VTCA from fatty acid oxidation (lower bars) and through PDH (upper bars). (d,e) Whole-body glycerol and palmitic acid oxidation. (f) Liver acetyl-CoA concentrations. Throughout the figure, the data are shown as the mean ± s.e.m. of n = 6 per group. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Statistical analyses were performed using two-tailed unpaired Student's t test. Asterisks under the lower bars represent comparisons of gluconeogenesis from pyruvate, asterisks over the upper bars represent comparisons of gluconeogenesis from glycerol and the uppermost asterisks represent comparisons with total gluconeogenesis.

  4. Matching plasma corticosterone in 3-d HFD-fed corticosterone-infused rats to that of rats with T1D drives excess lipolysis, gluconeogenesis and hyperglycemia.
    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.

    (a) Fasting plasma glucose in nondiabetic, saline-infused control rats and rats fed a HFD and infused with corticosterone (HFD-cort). (b) Hepatic gluconeogenesis from pyruvate (black or white bars) and glycerol (gray bars). (c) Fasting plasma insulin. (d) TCA cycle flux from fatty acid oxidation (lower bars) and through PDH (upper bars). (eg) Whole-body glycerol, fatty acid (palmitate) and acetate turnover. (h) Liver acetyl-CoA concentrations. Throughout the figure, the data are shown as the mean ± s.e.m. of n = 6 per group. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Statistical analyses were performed using two-tailed unpaired Student's t test.

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Author information

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

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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The authors declare no competing financial interests.

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