POMC neurons expressing leptin receptors coordinate metabolic responses to fasting via suppression of leptin levels

Leptin is critical for energy balance, glucose homeostasis, and for metabolic and neuroendocrine adaptations to starvation. A prevalent model predicts that leptin’s actions are mediated through pro-opiomelanocortin (POMC) neurons that express leptin receptors (LEPRs). However, previous studies have used prenatal genetic manipulations, which may be subject to developmental compensation. Here, we tested the direct contribution of POMC neurons expressing LEPRs in regulating energy balance, glucose homeostasis and leptin secretion during fasting using a spatiotemporally controlled Lepr expression mouse model. We report a dissociation between leptin’s effects on glucose homeostasis versus energy balance in POMC neurons. We show that these neurons are dispensable for regulating food intake, but are required for coordinating hepatic glucose production and for the fasting-induced fall in leptin levels, independent of changes in fat mass. We also identify a role for sympathetic nervous system regulation of the inhibitory adrenergic receptor (ADRA2A) in regulating leptin production. Collectively, our findings highlight a previously unrecognized role of POMC neurons in regulating leptin levels.

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Glucagon regulates hepatic mitochondrial function and biogenesis through FOXO1

Journal of Endocrinology ◽

10.1530/joe-19-0081 ◽

2019 ◽

Vol 241 (3) ◽

pp. 265-278

Author(s):

Wanbao Yang ◽

Hui Yan ◽

Quan Pan ◽

James Zheng Shen ◽

Fenghua Zhou ◽

...

Keyword(s):

Glucose Homeostasis ◽

Mitochondrial Function ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Complex Iii ◽

Dependent Manner ◽

Hepatic Glucose ◽

Patients With Diabetes ◽

High Level

Glucagon promotes hepatic glucose production maintaining glucose homeostasis in the fasting state. Glucagon maintains at high level in both diabetic animals and human, contributing to hyperglycemia. Mitochondria, a major place for glucose oxidation, are dysfunctional in diabetic condition. However, whether hepatic mitochondrial function can be affected by glucagon remains unknown. Recently, we reported that FOXO1 is an important mediator in glucagon signaling in control of glucose homeostasis. In this study, we further assessed the role of FOXO1 in the action of glucagon in the regulation of hepatic mitochondrial function. We found that glucagon decreased the heme production in a FOXO1-dependent manner, suppressed heme-dependent complex III (UQCRC1) and complex IV (MT-CO1) and inhibited hepatic mitochondrial function. However, the suppression of mitochondrial function by glucagon was largely rescued by deleting the Foxo1 gene in hepatocytes. Glucagon tends to reduce hepatic mitochondrial biogenesis by attenuating the expression of NRF1, TFAM and MFN2, which is mediated by FOXO1. In db/db mice, we found that hepatic mitochondrial function was suppressed and expression levels of UQCRC1, MT-CO1, NRF1 and TFAM were downregulated in the liver. These findings suggest that hepatic mitochondrial function can be impaired when hyperglucagonemia occurs in the patients with diabetes mellitus, resulting in organ failure.

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The role of autoregulation of the hepatic glucose production in man. Response to a physiologic decrement in plasma glucose

Diabetes ◽

10.2337/diabetes.35.2.186 ◽

1986 ◽

Vol 35 (2) ◽

pp. 186-191 ◽

Cited By ~ 2

Author(s):

I. Hansen ◽

R. Firth ◽

M. Haymond ◽

P. Cryer ◽

R. Rizza

Keyword(s):

Plasma Glucose ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Hepatic Glucose

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Regulation of hepatic glucose production during exercise in humans: role of sympathoadrenergic activity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.265.2.e275 ◽

1993 ◽

Vol 265 (2) ◽

pp. E275-E283 ◽

Cited By ~ 23

Author(s):

M. Kjaer ◽

K. Engfred ◽

A. Fernandes ◽

N. H. Secher ◽

H. Galbo

Keyword(s):

Plasma Glucose ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Constant Infusion ◽

Intense Exercise ◽

Nerve Activity ◽

Hepatic Glucose ◽

Sympathoadrenergic Activity ◽

Exercise In Humans

To investigate the role of sympathoadrenergic activity on glucose production (Ra) during exercise, eight healthy males bicycled 20 min at 41 +/- 2 and 74 +/- 4% maximal O2 uptake (VO2max; mean +/- SE) either without (control; Co) or with blockade of sympathetic nerve activity to liver and adrenal medulla by local anesthesia of the celiac ganglion (Bl). Epinephrine (Epi) was in some experiments infused during blockade to match (normal Epi) or exceed (high Epi) Epi levels during Co. A constant infusion of somatostatin and glucagon was given before and during exercise. At rest, insulin was infused at a rate maintaining euglycemia. During intense exercise, insulin infusion was halved to mimic physiological conditions. During exercise, Ra increased in Co from 14.4 +/- 1.0 to 27.8 +/- 3.0 mumol.min-1.kg-1 (41% VO2max) and to 42.3 +/- 5.2 (74% VO2max; P < 0.05). At 41% VO2max, plasma glucose decreased, whereas it increased during 74% VO2max. Ra was not influenced by Bl. In high Epi, Ra rose more markedly compared with control (P < 0.05), and plasma glucose did not fall during mild exercise and increased more during intense exercise (P < 0.05). Free fatty acid and glycerol concentrations were always lower during exercise with than without celiac blockade. We conclude that high physiological concentrations of Epi can enhance Ra in exercising humans, but normally Epi is not a major stimulus. The study suggests that neither sympathetic liver nerve activity is a major stimulus for Ra during exercise. The Ra response is enhanced by a decrease in insulin and probably by unknown stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

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Multiple metabolic effects of CGRP in conscious rats: role of glycogen synthase and phosphorylase

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.264.1.e1 ◽

1993 ◽

Vol 264 (1) ◽

pp. E1-E10 ◽

Cited By ~ 2

Author(s):

L. Rossetti ◽

S. Farrace ◽

S. B. Choi ◽

A. Giaccari ◽

L. Sloan ◽

...

Keyword(s):

Skeletal Muscle ◽

Glycogen Synthase ◽

Hepatic Glucose Production ◽

Glycogen Synthesis ◽

Plasma Concentrations ◽

Glucose Production ◽

Glucose Disposal ◽

Hepatic Glucose ◽

Intracellular Glucose

Calcitonin gene-related peptide (CGRP) is a neuropeptide that is released at the neuromuscular junction in response to nerve excitation. To examine the relationship between plasma CGRP concentration and intracellular glucose metabolism in conscious rats, we performed insulin (22 pmol.kg-1.min-1) clamp studies combined with the infusion of 0, 20, 50, 100, 200, and 500 pmol.kg-1.min-1 CGRP (plasma concentrations ranging from 2 x 10(-11) to 5 x 10(-9) M). CGRP antagonized insulin's suppression of hepatic glucose production at plasma concentrations (approximately 10(-10) M) that are only two- to fivefold its basal portal concentration. Insulin-mediated glucose disposal was decreased by 20-32% when CGRP was infused at 50 pmol.kg-1.min-1 (plasma concentration 3 x 10(-10) M) or more. The impairment in insulin-stimulated glycogen synthesis in skeletal muscle accounted for all of the CGRP-induced decrease in glucose disposal, while whole body glycolysis was increased despite the reduction in total glucose uptake. The muscle glucose 6-phosphate concentration progressively increased during the CGRP infusions. CGRP inhibited insulin-stimulated glycogen synthase in skeletal muscle with a 50% effective dose of 1.9 +/- 0.36 x 10(-10) M. This effect on glycogen synthase was due to a reduction in enzyme affinity for UDP-glucose, with no changes in the maximal velocity. In vitro CGRP stimulated both hepatic and skeletal muscle adenylate cyclase in a dose-dependent manner. These data suggest that 1) CGRP is a potent antagonist of insulin at the level of muscle glycogen synthesis and hepatic glucose production; 2) inhibition of glycogen synthase is its major biochemical action in skeletal muscle; and 3) these effects are present at concentrations of the peptide that may be in the physiological range for portal vein and skeletal muscle. These data underscore the potential role of CGRP in the physiological modulation of intracellular glucose metabolism.

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P0950EFFECT OF THYROID HORMONE TREATMENT ON RENAL REABSORPTION OF GLUCOSE IN ALLOXAN-INDUCED DIABETIC RATS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0950 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Gireesh Dayma

Keyword(s):

Blood Glucose ◽

Thyroid Hormone ◽

Glucose Homeostasis ◽

Hepatic Glucose Production ◽

Liver Perfusion ◽

Glucose Production ◽

Diabetic Rats ◽

Hepatic Glucose ◽

Glucose Output ◽

Renal Expression

Abstract Background and Aims The thyroid hormone (TH) plays an important role in glucose metabolism. Recently, we showed that the TH improves glycemia control by decreasing cytokines expression in the adipose tissue and skeletal muscle of alloxan-induced diabetic rats, which were also shown to present primary hypothyroidism. In this context, this study aims to investigate whether the chronic treatment of diabetic rats with T3 could affect other tissues that are involved in the control of glucose homeostasis, as the liver and kidney. Method Adult male Wistar rats were divided into nondiabetic, diabetic, and diabetic treated with T3 (1.5 ?g/100 g BW for 4 weeks). Diabetes was induced by alloxan monohydrate (150 mg/kg, BW, i.p.). Animals showing fasting blood glucose levels greater than 250 mg/dL were selected for the study. Results After treatment, we measured the blood glucose, serum T3, T4, TSH, and insulin concentration, hepatic glucose production by liver perfusion, liver PEPCK, GAPDH, and pAKT expression, as well as urine glucose concentration and renal expression of SGLT2 and GLUT2. T3 reduced blood glucose, hepatic glucose production, liver PEPCK, GAPDH, and pAKT content and the renal expression of SGLT2 and increased glycosuria. Conclusion Results suggest that the decreased hepatic glucose output and increased glucose excretion induced by T3 treatment are important mechanisms that contribute to reduce serum concentration of glucose, accounting for the improvement of glucose homeostasis control in diabetic rats.

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Glucagon Deficiency Reduces Hepatic Glucose Production and Improves Glucose Tolerance In Adult Mice

Endocrine Reviews ◽

10.1210/edrv.31.4.9983 ◽

2010 ◽

Vol 31 (4) ◽

pp. 606-606

Author(s):

Aidan S. Hancock ◽

Aiping Du ◽

Jingxuan Liu ◽

Mayumi Miller ◽

Catherine L. May

Keyword(s):

Glucose Homeostasis ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Postprandial Glucose ◽

Glucagon Receptor ◽

Glucose Levels ◽

Adult Mice ◽

Hepatic Glucose ◽

Knockout Animals

Abstract The major role of glucagon is to promote hepatic gluconeogenesis and glycogenolysis to raise blood glucose levels during hypoglycemic conditions. Several animal models have been established to examine the in vivo function of glucagon in the liver through attenuation of glucagon via glucagon receptor knockout animals and pharmacological interventions. To investigate the consequences of glucagon loss to hepatic glucose production and glucose homeostasis, we derived mice with a pancreas specific ablation of the α-cell transcription factor, Arx, resulting in a complete loss of the glucagon-producing pancreatic α-cell. Using this model, we found that glucagon is not required for the general health of mice but is essential for total hepatic glucose production. Our data clarifies the importance of glucagon during the regulation of fasting and postprandial glucose homeostasis.

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Glucagon enhances the direct suppressive effect of insulin on hepatic glucose production in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.272.3.e371 ◽

1997 ◽

Vol 272 (3) ◽

pp. E371-E378 ◽

Cited By ~ 4

Author(s):

G. F. Lewis ◽

M. Vranic ◽

A. Giacca

Keyword(s):

Type I Diabetes ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Insulin Delivery ◽

Suppressive Effect ◽

Type I ◽

Constant Rate ◽

Hepatic Glucose ◽

Infusion Method

The present study examines the role of glucagon in modulating the hepatic and extrahepatic effects of insulin on hepatic glucose production (HGP). We infused glucagon at a constant rate (0.65 ng x kg(-1) x min(-1)) during equimolar portal and peripheral insulin delivery in seven healthy males by our previously published tolbutamide infusion method. In contrast to our previous study, in which glucagon fell by approximately 30% during hyperinsulinemia and suppression of HGP was significantly greater with equimolar peripheral than with portal insulin delivery, HGP was actually suppressed to a lesser extent with peripheral insulin delivery (69 +/- 10%) than when insulin was delivered portally (76 +/- 5%, P < 0.05). To further examine whether glucagon was enhancing the effect of portal insulin, in four additional individuals HGP was suppressed to a greater extent during a tolbutamide infusion when glucagon was administered continuously throughout the basal and hyperinsulinemic periods than when glucagon was infused during the basal period only; HGP suppressed by 63 +/- 3 vs. 52 +/- 3%, respectively, P = 0.02). Tolbutamide had no effect on HGP when infused into three C-peptide-negative individuals with type I diabetes during a low-dose insulin and glucagon infusion. These data suggest that glucagon levels are an important determinant of the balance between insulin's direct and indirect effects on HGP, with glucagon likely potentiating the direct hepatic effect of insulin.

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