Hypothalamic glucagon signaling inhibits hepatic glucose production

Mighiu, Patricia I.; Yue, Jessica T.Y.; Filippi, B; Abraham, Mona A.; Chari, Madhu; Lam, Carol K.L.; Yang, Clair S.; Christian, Nikita R; Charron, Maureen J.; Lam, Tony K.T.

doi:10.1038/nm.3115

Cited by 103 publications

(129 citation statements)

References 47 publications

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“…Hormones such as insulin, glucagon, and leptin have been shown to regulate hepatic glucose metabolism through both central and peripheral actions (34,35). In this study, we provide several lines of evidence demonstrating that the stimulatory effect of FGF21 on hepatic gluconeogenesis is mainly mediated by its central actions on hypothalamic neurons.…”

Section: Discussionmentioning

confidence: 68%

FGF21 Maintains Glucose Homeostasis by Mediating the Cross Talk Between Liver and Brain During Prolonged Fasting

et al. 2014

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Hepatic gluconeogenesis is a main source of blood glucose during prolonged fasting and is orchestrated by endocrine and neural pathways. Here we show that the hepatocytesecreted hormone fibroblast growth factor 21 (FGF21) induces fasting gluconeogenesis via the brain-liver axis. Prolonged fasting induces activation of the transcription factor peroxisome proliferator-activated receptor a (PPARa) in the liver and subsequent hepatic production of FGF21, which enters into the brain to activate the hypothalamic-pituitary-adrenal (HPA) axis for release of corticosterone, thereby stimulating hepatic gluconeogenesis. Fasted FGF21 knockout (KO) mice exhibit severe hypoglycemia and defective hepatic gluconeogenesis due to impaired activation of the HPA axis and blunted release of corticosterone, a phenotype similar to that observed in PPARa KO mice. By contrast, intracerebroventricular injection of FGF21 reverses fasting hypoglycemia and impairment in hepatic gluconeogenesis by restoring corticosterone production in both FGF21 KO and PPARa KO mice, whereas all these central effects of FGF21 were abrogated by blockage of hypothalamic FGF receptor-1. FGF21 acts directly on the hypothalamic neurons to activate the mitogen-activated protein kinase extracellular signalrelated kinase 1/2 (ERK1/2), thereby stimulating the expression of corticotropin-releasing hormone by activation of the transcription factor cAMP response element binding protein. Therefore, FGF21 maintains glucose homeostasis during prolonged fasting by fine tuning the interorgan cross talk between liver and brain.Hepatic gluconeogenesis is tightly controlled by counterregulatory hormones such as glucagon, cortisol, and insulin, via regulating the expression of key gluconeogenic enzymes, including glucose 6 phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Fibroblast growth factor 21 (FGF21), a metabolic regulator mainly secreted from the liver in response to fasting and starvation under the control of the nuclear receptor peroxisome proliferatoractivated receptor a (PPARa), plays a critical role in maintaining energy homeostasis and insulin sensitivity in both rodents and nonhuman primates (1-6). A therapeutic dose of FGF21 decreased blood glucose in diabetic animals without causing hypoglycemia (4). FGF21 has also been shown to act as a key downstream effector of PPARa, mediating several metabolic adaptation responses to starvation, including hepatic fatty acid oxidation, ketogenesis, and growth hormone resistance (1,2,7). In addition, FGF21 is implicated in hepatic gluconeogenesis, although it remains controversial whether hepatocytes are a direct action site of FGF21 (8,9). There is an obvious dichotomy between the effects of endogenous FGF21 and pharmacological actions of the recombinant peptide with respect to hepatic metabolism (4,6,9).FGF21 can cross the blood-brain barrier (10) and is detectable in both human and rodent cerebrospinal fluid (10,11). Continuous intracerebroventricular injection of FGF21 into obese rats increases energy e...

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Section: Discussionmentioning

confidence: 68%

FGF21 Maintains Glucose Homeostasis by Mediating the Cross Talk Between Liver and Brain During Prolonged Fasting

et al. 2014

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“…By contrast, activation of PKA in MBH inhibits HGP and resembles the effects of glucagon injection to the hypothalamus. The glucagon-induced activation of hypothalamic PKA and inhibition of HGP are both attenuated in rats fed a high-fat diet, whereas activation of PKA by Sp-cAMPS infusion to MBH can still efficiently inhibit HGP in these rats (Mighiu et al 2013). These findings suggest that hypothalamic glucagon resistance contributes to increased HGP and hyperglycemia in diabetes and obesity and that pharmacological activation of PKA in MBH can bypass the glucagon resistance with therapeutic potential for diabetes treatment.…”

Section: Camp/pka In the Brainmentioning

confidence: 84%

“…In hypothalamic neurons, cAMP signaling is modulated by several hormones including leptin and insulin to affect food intake (Zhao 2005). A recent study found that glucagon acts in the hypothalamus to inhibit HGP by a PKA-dependent mechanism (Mighiu et al 2013). Inhibition of PKA activity in the mediobasal hypothalamus (MBH) abolishes the suppressive effect of glucagon on HGP and leads to increased i.v.…”

Section: Camp/pka In the Brainmentioning

confidence: 99%

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Yang

2016

Journal of Molecular Endocrinology

143

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In mammals, cyclic adenosine monophosphate (cAMP) is an intracellular second messenger that is usually elicited by binding of hormones and neurotransmitters to G protein-coupled receptors (GPCRs). cAMP exerts many of its physiological effects by activating cAMPdependent protein kinase (PKA), which in turn phosphorylates and regulates the functions of downstream protein targets including ion channels, enzymes, and transcription factors. cAMP/PKA signaling pathway regulates glucose homeostasis at multiple levels including insulin and glucagon secretion, glucose uptake, glycogen synthesis and breakdown, gluconeogenesis, and neural control of glucose homeostasis. This review summarizes recent genetic and pharmacological studies concerning the regulation of glucose homeostasis by cAMP/PKA in pancreas, liver, skeletal muscle, adipose tissues, and brain. We also discuss the strategies for targeting cAMP/PKA pathway for research and potential therapeutic treatment of type 2 diabetes mellitus (T2D).

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“…In addition to the central actions mentioned above, it has been suggested that the satiety effect of glucagon may involve the suppression of the orexigenic hormone ghrelin via the hypothalamic -pituitary axis (133) . It has recently been reported that hypothalamic glucagon signalling inhibits hepatic glucose production and that the central resistance to this hormone might be involved in the hyperglycaemia that characterises diabetes (134) . Considerable evidence supports the role of glucagon as a thermogenic agent, thereby favouring the body's energy expenditure.…”

Section: Effects Of Glucagon On Food Intake Body Weight and Body Energymentioning

confidence: 99%

Nutrient regulation of glucagon secretion: involvement in metabolism and diabetes

et al. 2014

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Glucose homeostasis is precisely regulated by glucagon and insulin, which are released by pancreatic a-and b-cells, respectively. While b-cells have been the focus of intense research, less is known about a-cell function and the actions of glucagon. In recent years, the study of this endocrine cell type has experienced a renewed drive. The present review contains a summary of established concepts as well as new information about the regulation of a-cells by glucose, amino acids, fatty acids and other nutrients, focusing especially on glucagon release, glucagon synthesis and a-cell survival. We have also discussed the role of glucagon in glucose homeostasis and in energy and lipid metabolism as well as its potential as a modulator of food intake and body weight. In addition to the well-established action on the liver, we discuss the effects of glucagon in other organs, where the glucagon receptor is expressed. These tissues include the heart, kidneys, adipose tissue, brain, small intestine and the gustatory epithelium. Alterations in a-cell function and abnormal glucagon concentrations are present in diabetes and are thought to aggravate the hyperglycaemic state of diabetic patients. In this respect, several experimental approaches in diabetic models have shown important beneficial results in improving hyperglycaemia after the modulation of glucagon secretion or action. Moreover, glucagon receptor agonism has also been used as a therapeutic strategy to treat obesity.

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Hypothalamic glucagon signaling inhibits hepatic glucose production

Cited by 103 publications

References 47 publications

FGF21 Maintains Glucose Homeostasis by Mediating the Cross Talk Between Liver and Brain During Prolonged Fasting

FGF21 Maintains Glucose Homeostasis by Mediating the Cross Talk Between Liver and Brain During Prolonged Fasting

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Nutrient regulation of glucagon secretion: involvement in metabolism and diabetes

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