The Glucagon Receptor Is Required for the Adaptive Metabolic Response to Fasting

Longuet, Christine; Sinclair, Elaine M.; Maida, Adriano; Baggio, Laurie L.; Maziarz, Marlena; Charron, Maureen J.; Drucker, Daniel J.

doi:10.1016/j.cmet.2008.09.008

Cited by 222 publications

(238 citation statements)

References 47 publications

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“…Although glucagon has been reported to inhibit lipid secretion from hepatocytes [33], circulating levels of glucagon were not reduced following sitagliptin administration in our current experiments. Furthermore D-Ala 2 -GIP did not reduce, but actually promoted postprandial triacylglycerol and ApoB-48 secretion.…”

Section: Discussionmentioning

confidence: 48%

The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion in hamsters and mice

et al. 2009

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Aims/hypothesis Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors attenuate postprandial lipaemia through mechanisms that remain unclear. As dyslipidaemia is a contributing risk factor for cardiovascular disease in type 2 diabetes, we examined the mechanisms linking pharmacological and physiological regulation of GLP-1 action to control of postprandial lipid metabolism.Methods Postprandial lipid synthesis and secretion were assessed in normal and fructose-fed hamsters and in wildtype mice that were treated with or without sitagliptin. Apolipoprotein B-48 (ApoB-48) synthesis and secretion were also examined in primary enterocyte cultures. The importance of exogenous vs endogenous GLP-1R signalling for regulation of intestinal lipoprotein synthesis and secretion was assessed in mice and hamsters treated with the GLP-1R agonist exendin-4, the GLP-1R antagonist exendin(9-39) and in Glp1r Electronic supplementary material The online version of this article

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Section: Discussionmentioning

confidence: 48%

The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion in hamsters and mice

et al. 2009

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“…NMR isotopomer analyses show that PGC-1␣-KO liver has reductions in fatty acid oxidation, ketogenesis, TCA flux, and gluconeogenesis that mirror those in the FGF21-KO liver (4). Because glucagon and its downstream effector, cAMP, induce PGC-1␣ and gluconeogenic gene expression during the early stages of the fasting response (24,35), we propose that FGF21 maintains the expression of these genes during prolonged fasting and starvation.…”

Section: Discussionmentioning

confidence: 97%

FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response

Potthoff

Inagaki

Satapati

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

639

570

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The liver plays a crucial role in mobilizing energy during nutritional deprivation. During the early stages of fasting, hepatic glycogenolysis is a primary energy source. As fasting progresses and glycogen stores are depleted, hepatic gluconeogenesis and ketogenesis become major energy sources. Here, we show that fibroblast growth factor 21 (FGF21), a hormone that is induced in liver by fasting, induces hepatic expression of peroxisome proliferatoractivated receptor ␥ coactivator protein-1␣ (PGC-1␣), a key transcriptional regulator of energy homeostasis, and causes corresponding increases in fatty acid oxidation, tricarboxylic acid cycle flux, and gluconeogenesis without increasing glycogenolysis. Mice lacking FGF21 fail to fully induce PGC-1␣ expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis. These results reveal an unexpected relationship between FGF21 and PGC-1␣ and demonstrate an important role for FGF21 in coordinately regulating carbohydrate and fatty acid metabolism during the progression from fasting to starvation.lipid metabolism ͉ liver ͉ gluconeogenesis ͉ glycogenolysis ͉ ketogenesis I n mammals, the liver plays a crucial role in maintaining systemic energy balance during fasting and starvation through coordinate effects on carbohydrate and lipid metabolism. During the early stages of fasting, the liver mobilizes glucose from its glycogen stores. As fasting progresses and glycogen reserves are depleted, the liver oxidizes fat to provide both energy for gluconeogenesis and substrate for ketogenesis. This synchronization of hepatic lipid and carbohydrate metabolism is critical for the normal fasting response; disruption of either one of these pathways has profound effects on the other (1-4).Hormones such as glucagon, catecholamines, and glucocorticoids have important roles in controlling substrate utilization and maintaining energy balance during fasting. Recently, the hormone fibroblast growth factor 21 (FGF21) was shown to be induced in the liver during fasting (5-7). FGF21 is an unusual FGF family member in that it lacks the conventional heparinbinding domain (8) and thus can diffuse away from its tissue of origin and function as a hormone. FGF21 signals through cell-surface receptors composed of classic FGF receptors complexed with ␤-klotho, a membrane-spanning protein (9-14). Induction of FGF21 during fasting occurs through a mechanism that requires peroxisome proliferator-activated receptor ␣ (PPAR␣) (5-7). FGF21 has diverse metabolic actions that include stimulating hepatic fatty acid oxidation and ketogenesis (5,6,15) and blocking the growth hormone signaling pathway (16). FGF21 also sensitizes mice to torpor, a short-term hibernation-like state of regulated hypothermia (6). Pharmacologic administration of FGF21 to insulin-resistant rodents and monkeys improves glucose tolerance and reduces plasma insulin and triglyceride concentrations (15,17).Peroxisome proliferator-activated receptor ␥ coactivator protein-1␣ (PGC-1␣) is a transcriptional coactivator ...

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“…In rodents glucagon seems to stimulate Fgf-21 expression in vitro and in vivo [12][13][14][15], and these effects are somewhat augmented by NEFA [15]. However, another study reported that glucagon fails to stimulate hepatic Fgf-21 mRNA expression in rodents [16].…”

Section: Introductionmentioning

confidence: 99%

Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis?

et al. 2012

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Aims/hypothesis Glucagon reduces body weight by modifying food intake, glucose/lipid metabolism and energy expenditure. All these physiological processes are also controlled by fibroblast growth factor 21 (FGF-21), a circulating hepatokine that improves the metabolic profile in obesity and type 2 diabetes. Animal experiments have suggested a possible interaction between glucagon and FGF-21 however, the metabolic consequences of this crosstalk are not understood. Methods The effects of exogenous glucagon on plasma FGF-21 levels and lipolysis were evaluated in healthy volunteers and humans with type 1 diabetes, as well as in rodents with streptozotocin (STZ)-induced insulinopenic diabetes. In vitro, the role of glucagon on FGF-21 secretion and lipolysis was studied using isolated primary rat hepatocytes and adipocytes. Fgf-21 expression in differentiated rat pre-adipocytes was suppressed by small interfering RNA and released FGF-21 was immunoneutralised by polyclonal antibodies. Results Glucagon induced lipolysis in healthy human volunteers, patients with type 1 diabetes, mice and rats with STZ-induced insulinopenic diabetes, and in adipocytes isolated from diabetic and non-diabetic animals. In addition, glucagon increased circulating FGF-21 in healthy humans and rodents, as well as in patients with type 1 diabetes, and insulinopenic rodents. Glucagon stimulated FGF-21 secretion from isolated primary hepatocytes and adipocytes derived from animals with insulinopenic diabetes. Furthermore, FGF-21 stimulated lipolysis in primary adipocytes isolated from non-diabetic and diabetic rats. Reduction of Fgf-21 expression (by approximately 66%) or immunoneutralisation of released FGF-21 markedly attenuated glucagon-stimulated lipolysis in adipocytes. Conclusions/interpretation These results indicate that glucagon increases circulating FGF-21 independently of endogenous insulin levels. FGF-21 participates in glucagon-induced stimulation of lipolysis.

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The Glucagon Receptor Is Required for the Adaptive Metabolic Response to Fasting

Cited by 222 publications

References 47 publications

The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion in hamsters and mice

The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion in hamsters and mice

FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response

Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis?

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