Insulin Receptor Signaling in POMC, but Not AgRP, Neurons Controls Adipose Tissue Insulin Action - PubMed (original) (raw)

. 2017 Jun;66(6):1560-1571.

doi: 10.2337/db16-1238. Epub 2017 Apr 6.

Affiliations

Insulin Receptor Signaling in POMC, but Not AgRP, Neurons Controls Adipose Tissue Insulin Action

Andrew C Shin et al. Diabetes. 2017 Jun.

Abstract

Insulin is a key regulator of adipose tissue lipolysis, and impaired adipose tissue insulin action results in unrestrained lipolysis and lipotoxicity, which are hallmarks of the metabolic syndrome and diabetes. Insulin regulates adipose tissue metabolism through direct effects on adipocytes and through signaling in the central nervous system by dampening sympathetic outflow to the adipose tissue. Here we examined the role of insulin signaling in agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) neurons in regulating hepatic and adipose tissue insulin action. Mice lacking the insulin receptor in AgRP neurons (AgRP IR KO) exhibited impaired hepatic insulin action because the ability of insulin to suppress hepatic glucose production (hGP) was reduced, but the ability of insulin to suppress lipolysis was unaltered. To the contrary, in POMC IR KO mice, insulin lowered hGP but failed to suppress adipose tissue lipolysis. High-fat diet equally worsened glucose tolerance in AgRP and POMC IR KO mice and their respective controls but increased hepatic triglyceride levels only in POMC IR KO mice, consistent with impaired lipolytic regulation resulting in fatty liver. These data suggest that although insulin signaling in AgRP neurons is important in regulating glucose metabolism, insulin signaling in POMC neurons controls adipose tissue lipolysis and prevents high-fat diet-induced hepatic steatosis.

© 2017 by the American Diabetes Association.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Deletion of IR in AgRP neurons impairs the ability of insulin to suppress HGP without affecting adipose tissue insulin action. A: Schematic representation of hyperinsulinemic-euglycemic clamp protocol in mice. B: Blood glucose of AgRP IR WT and AgRP IR KO mice before and during the clamp period. C: GIR required to maintain euglycemia during the hyperinsulinemic clamps. D: Mean GIR. E: _R_d of glucose. F: hGP during basal and clamp periods. G: Percentage suppression of hGP. H: _R_a of glycerol in plasma at basal and steady state during the clamp period. Plasma levels of insulin (I), TGs (J), glycerol (K), and NEFA (L) during basal and clamp periods. M: IL-6 mRNA expressions in liver after hyperinsulinemic clamps. n ≥6 per group. Values are mean ± SEM. *P < 0.05 compared with WT or basal value of respective group.

Figure 2

Figure 2

Mice lacking IR in POMC neurons maintain normal hepatic insulin action but display an impaired ability of insulin to suppress lipolysis. A: Blood glucose before and during the clamp period. B: GIR required to maintain euglycemia during the hyperinsulinemic clamps. C: Mean GIR. D: _R_d of glucose. E: hGP during basal and clamp periods. F: Percentage suppression of hGP. G: _R_a of glycerol in plasma at basal and steady state during the clamp period. Plasma levels of insulin (H), TGs (I), glycerol (J), and NEFA (K) during basal and clamp periods. L: IL-6 mRNA expressions in liver after pancreatic clamps. n ≥6 per group. Values are mean ± SEM. *P < 0.05 compared with WT or basal value of respective group.

Figure 3

Figure 3

POMC IR KO mice have increased fatty acid utilization rates. A: Energy expenditure of AgRP IR KO, POMC IR KO mice, and their respective WT littermates, as measured by total VO2 consumption in metabolic chambers via indirect calorimetry. B: Average VO2 between groups. C: RER measurement. D: Average RER. E: Locomotor activity in metabolic chambers. F: Rectal temperature (°C) of mice during cold tolerance test at 4°C for 2 h. n ≥6 per group. Values are mean ± SEM. *P < 0.05 compared with respective WT.

Figure 4

Figure 4

Chronic HFD feeding leads to hepatic steatosis only in POMC IR KO mice without affecting glucose tolerance. A: Body weight in mice lacking IR in AgRP or POMC neurons after 5 months of 60% HFD feeding. B: Whole-body glucose metabolism of AgRP IR KO mice and POMC IR KO mice as assessed by glucose tolerance test (intraperitoneal injection of 1.5 g/kg body wt). C: Plasma levels of TGs, glycerol, and NEFA of AgRP IR KO mice at the time of sacrifice. D: TG levels in liver of AgRP IR KO mice. E: Plasma levels of TGs, glycerol, and NEFA of POMC IR KO mice at the time of sacrifice. F: TG levels in liver of POMC IR KO mice. n ≥6 per group. Values are mean ± SEM. *P < 0.05 compared with respective WT.

Figure 5

Figure 5

Proposed mechanism. Insulin signaling in AgRP neurons suppresses hGP but does not alter adipose tissue lipolysis. On the other hand, insulin signaling in POMC neurons does not regulate hGP but does restrain adipose tissue lipolysis. Chronic HFD feeding in mice with deletion of IR in POMC neurons exacerbates the lipolysis and increases the flux of free fatty acids (FFAs) into the liver, increasing susceptibility to HFD-induced hepatic steatosis. 3V, 3rd ventricle.

Similar articles

Cited by

References

    1. Krashes MJ, Shah BP, Koda S, Lowell BB. Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metab 2013;18:588–595 - PMC - PubMed
    1. Aponte Y, Atasoy D, Sternson SM. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci 2011;14:351–355 - PMC - PubMed
    1. Krashes MJ, Koda S, Ye C, et al. . Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest 2011;121:1424–1428 - PMC - PubMed
    1. Bewick GA, Gardiner JV, Dhillo WS, et al. . Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J 2005;19:1680–1682 - PubMed
    1. Gropp E, Shanabrough M, Borok E, et al. . Agouti-related peptide-expressing neurons are mandatory for feeding. Nat Neurosci 2005;8:1289–1291 - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources