Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions

Habegger, Kirk M.; Stemmer, Kerstin; Cheng, Christine; Müller, Timo; Heppner, Kristy M.; Ottaway, Nickki; Holland, Jenna; Hembree, Jazzminn; Smiley, David L.; Gelfanov, Vasily; Krishna, Radha; Arafat, Ayman M.; Konkar, Anish; Belli, Sara; Kapps, Martin; Woods, Stephen C.; Hofmann, Susanna M.; D’Alessio, David A.; Pfluger, Paul T.; Pérez-Tilve, Diego; Seeley, Randy J.; Konishi, Morichika; Itoh, Nobuyujki; Kharitonenkov, Alexei; Spranger, Joachim; DiMarchi, Richard D.; Tschöp, Matthias H.

doi:10.2337/db12-1116

Cited by 209 publications

(219 citation statements)

References 34 publications

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“…Omar et al (19) recently provided data supporting a contributing role for GLP-1 in glucose homeostasis of STZ-treated Gcgr 2/2 mice by showing animals administered the GLP-1 receptor (GLP-1R) peptide antagonist, exendin-4 , display poorer glucose tolerance compared with animals that had not received the antagonist. This report also indicated circulating levels of fibroblast growth factor 21 (FGF21) are increased in Gcgr 2/2 mice, a finding paradoxical to other studies showing activation of the GCGR increases hepatic and circulating FGF21 levels (20,21). The combination of exendin-4 and FGF21 antisera worsened the glucose excursion for animals undergoing an oral glucose tolerance test (OGTT) (19 mice and in insulinopenic wild-type and Glp-1r 2/2 animals treated with a high-affinity GCGR antagonist antibody.…”

contrasting

confidence: 51%

Absence of Glucagon and Insulin Action Reveals a Role for the GLP-1 Receptor in Endogenous Glucose Production

et al. 2014

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The absence of insulin results in oscillating hyperglycemia and ketoacidosis in type 1 diabetes. Remarkably, mice genetically deficient in the glucagon receptor (Gcgr) are refractory to the pathophysiological symptoms of insulin deficiency, and therefore, studies interrogating this unique model may uncover metabolic regulatory mechanisms that are independent of insulin. A significant feature of Gcgr-null mice is the high circulating concentrations of GLP-1. Hence, the objective of this report was to investigate potential noninsulinotropic roles of GLP-1 in mice where GCGR signaling is inactivated. For these studies, pancreatic β-cells were chemically destroyed by streptozotocin (STZ) in Gcgr−/−:Glp-1r−/− mice and in Glp-1r−/− animals that were subsequently treated with a high-affinity GCGR antagonist antibody that recapitulates the physiological state of Gcgr ablation. Loss of GLP-1 action substantially worsened nonfasting glucose concentrations and glucose tolerance in mice deficient in, and undergoing pharmacological inhibition of, the GCGR. Further, lack of the Glp-1r in STZ-treated Gcgr−/− mice elevated rates of endogenous glucose production, likely accounting for the differences in glucose homeostasis. These results support the emerging hypothesis that non–β-cell actions of GLP-1 analogs may improve metabolic control in patients with insulinopenic diabetes.

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confidence: 51%

Absence of Glucagon and Insulin Action Reveals a Role for the GLP-1 Receptor in Endogenous Glucose Production

et al. 2014

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“…All these effects were attributed to a glucagon-induced release of FGF21, which has lipolytic activity. Actually, recent reports demonstrate that FGF21 also mediates other different glucagon actions, as we previously commented (147) . Given that the lipolytic action of glucagon is blunted in denervated rats, its effect on adipose tissue has also been associated with sympathetic signals (156) .…”

Section: Other Effects Of Glucagonmentioning

confidence: 99%

“…In the present study, the augmented energy expenditure was attributed to glucagon alone. Similarly, chronic glucagon receptor agonism in dietinduced obese mice lowered food intake, body weight, fat mass and cholesterolaemia while increasing energy expenditure (147) . The actions of glucagon were mediated by FGF21.…”

Section: Therapeutic Potential Of Modulating Glucagon Secretion and Amentioning

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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“…These results demonstrate that hepatic MKP-1 is required for the transcriptional expression of FGF21 in hepatocytes and implies that MAPK activity suppresses FGF21 transcriptional responsiveness. To identify which MAPK suppresses FGF21 expression, hepatocytes from Mkp-1 fl/fl mice were transiently transfected with the FGF21 luciferase reporter and were preincubated with MAPK inhibitors of p38 MAPK (SB203580), JNK (SP60015), and MEK (U0126) prior to stimulation with glucagon to promote both the expression of MKP-1 and FGF21 (32,33). We found that inhibition of p38 MAPK significantly relieved suppression of FGF21 promoter activity (Fig.…”

Section: Generation Of Liver-specific-mkp-1-deficient Micementioning

confidence: 99%

Hepatic Mitogen-Activated Protein Kinase Phosphatase 1 Selectively Regulates Glucose Metabolism and Energy Homeostasis

Lawan

Zhang

Gatzke

et al. 2015

Molecular and Cellular Biology

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The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH 2 -terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver-specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis. O besity is a major problem globally, and its incidence is increasing at an alarming rate (1). Obesity predisposes to the development of nonalcoholic fatty liver disease (NAFLD), which is a spectrum of liver-related pathologies that encompasses steatosis, nonalcoholic steatosis, and nonalcoholic steatohepatitis (2). The development of hepatosteatosis arises as a result of an imbalance between triglyceride deposition and removal. Epidemiologically, NAFLD is associated with type 2 diabetes, suggesting that hepatosteatosis and the development of insulin resistance are causally linked (2). However, both genetic mouse models and clinical data suggest dissociation of hepatosteatosis from insulin resistance, arguing against the existence of such a causal link (3). Several proposed mechanisms have been put forth to explain the relationship between hepatosteatosis and insulin resistance. One mechanism proposes that type 2 diabetes results in hyperinsulinemia, which promotes hepatic lipogenesis and thus hepatosteatosis. Dysfunction in hepatic lipid metabolism and lipotoxicity have also been proposed to activate serine/threonine kinases that subsequently lead to the failure of insulin to signal (4).The actions of kinases in physiological and pathophysiological metabolic pathways have been studied extensively (5, 6). In particular, the mitogen-activated protein kinase (MAPK) pathway is an established regulator of hepatic metabolism (7-10). The stressresponsive MAPK c-Jun NH 2 -terminal kinase 1 (JNK1), when deleted specifically in the liver, results in the development of hepatosteatosis, enhanced hepatic glucose produ...

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Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions

Cited by 209 publications

References 34 publications

Absence of Glucagon and Insulin Action Reveals a Role for the GLP-1 Receptor in Endogenous Glucose Production

Absence of Glucagon and Insulin Action Reveals a Role for the GLP-1 Receptor in Endogenous Glucose Production

Nutrient regulation of glucagon secretion: involvement in metabolism and diabetes

Hepatic Mitogen-Activated Protein Kinase Phosphatase 1 Selectively Regulates Glucose Metabolism and Energy Homeostasis

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