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The Amplifying Pathway of the β-Cell Contributes to Diet-induced Obesity*

  • Laurène Vetterli
    Affiliations
    Department of Cell Physiology and Metabolism and Faculty Diabetes Center, Geneva University Medical Centre, 1211 Geneva 4, Switzerland
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  • Stefania Carobbio
    Affiliations
    Department of Cell Physiology and Metabolism and Faculty Diabetes Center, Geneva University Medical Centre, 1211 Geneva 4, Switzerland
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  • Francesca Frigerio
    Affiliations
    Department of Cell Physiology and Metabolism and Faculty Diabetes Center, Geneva University Medical Centre, 1211 Geneva 4, Switzerland
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  • Melis Karaca
    Affiliations
    Department of Cell Physiology and Metabolism and Faculty Diabetes Center, Geneva University Medical Centre, 1211 Geneva 4, Switzerland
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  • Pierre Maechler
    Correspondence
    To whom correspondence should be addressed: Dept. of Cell Physiology and Metabolism, University Medical Centre, 1 Rue Michel-Servet, 1211 Geneva 4, Switzerland. Tel.: 41-22-379-55-54.
    Affiliations
    Department of Cell Physiology and Metabolism and Faculty Diabetes Center, Geneva University Medical Centre, 1211 Geneva 4, Switzerland
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  • Author Footnotes
    * This work was supported by the State of Geneva and the Swiss National Science Foundation (to P. M.). The authors declare that they have no conflicts of interest with the contents of this article.
    This article contains supplemental Table S1.
Open AccessPublished:May 02, 2016DOI:https://doi.org/10.1074/jbc.M115.707448
      Efficient energy storage in adipose tissues requires optimal function of the insulin-producing β-cell, whereas its dysfunction promotes diabetes. The associated paradox related to β-cell efficiency is that excessive accumulation of fat in adipose tissue predisposes for type 2 diabetes. Insulin exocytosis is regulated by intracellular metabolic signal transduction, with glutamate dehydrogenase playing a key role in the amplification of the secretory response. Here, we used mice with β-cell-selective glutamate dehydrogenase deletion (βGlud1−/−), lacking an amplifying pathway of insulin secretion. As opposed to control mice, βGlud1−/− animals fed a high calorie diet maintained glucose tolerance and did not develop diet-induced obesity. Islets of βGlud1−/− mice did not increase their secretory response upon high calorie feeding, as did islets of control mice. Inhibited adipose tissue expansion observed in knock-out mice correlated with lower expression of genes responsible for adipogenesis. Rather than being efficiently stored, lipids were consumed at a higher rate in βGlud1−/− mice compared with controls, in particular during food intake periods. These results show that reduced β-cell function prior to high calorie feeding prevented diet-induced obesity.

      Introduction

      Pancreatic β-cells produce the hormone insulin that is essential for glucose homeostasis. Upon nutrient stimulation, elevation of cytosolic calcium in the β-cell results from the closure of potassium channels and is the primary and necessary signal for insulin exocytosis (
      • Ashcroft F.M.
      K(ATP) channels and insulin secretion: a key role in health and disease.
      ). Then increasing the magnitude of insulin secretion in response to glucose stimulation requires amplification of the calcium signal supported by metabolism-derived additive factors (
      • Maechler P.
      Mitochondrial function and insulin secretion.
      ). The mitochondrial enzyme glutamate dehydrogenase (GDH),
      The abbreviations used are: GDH
      glutamate dehydrogenase
      HFD
      high fat diet
      ANOVA
      analysis of variance.
      encoded by the Glud1 gene (
      • Michaelidis T.M.
      • Tzimagiorgis G.
      • Moschonas N.K.
      • Papamatheakis J.
      The human glutamate dehydrogenase gene family: gene organization and structural characterization.
      ), has been shown to participate to the development of the secretory response (
      • Carobbio S.
      • Frigerio F.
      • Rubi B.
      • Vetterli L.
      • Bloksgaard M.
      • Gjinovci A.
      • Pournourmohammadi S.
      • Herrera P.L.
      • Reith W.
      • Mandrup S.
      • Maechler P.
      Deletion of glutamate dehydrogenase in β-cells abolishes part of the insulin secretory response not required for glucose homeostasis.
      ). Specifically, GDH is required for the amplifying pathway of glucose-stimulated insulin secretion in the β-cell (
      • Vetterli L.
      • Carobbio S.
      • Pournourmohammadi S.
      • Martin-Del-Rio R.
      • Skytt D.M.
      • Waagepetersen H.S.
      • Tamarit-Rodriguez J.
      • Maechler P.
      Delineation of glutamate pathways and secretory responses in pancreatic islets with β-cell specific abrogation of the glutamate dehydrogenase.
      ), providing permissive levels of glutamate to the cytosolic compartment and the exocytotic machinery (
      • Casimir M.
      • Lasorsa F.M.
      • Rubi B.
      • Caille D.
      • Palmieri F.
      • Meda P.
      • Maechler P.
      Mitochondrial glutamate carrier GC1 as a newly identified player in the control of glucose-stimulated insulin secretion.
      ,
      • Ferdaoussi M.
      • Dai X.
      • Jensen M.V.
      • Wang R.
      • Peterson B.S.
      • Huang C.
      • Ilkayeva O.
      • Smith N.
      • Miller N.
      • Hajmrle C.
      • Spigelman A.F.
      • Wright R.C.
      • Plummer G.
      • Suzuki K.
      • Mackay J.P.
      • et al.
      Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells.
      ,
      • Gheni G.
      • Ogura M.
      • Iwasaki M.
      • Yokoi N.
      • Minami K.
      • Nakayama Y.
      • Harada K.
      • Hastoy B.
      • Wu X.
      • Takahashi H.
      • Kimura K.
      • Matsubara T.
      • Hoshikawa R.
      • Hatano N.
      • Sugawara K.
      • et al.
      Glutamate acts as a key signal linking glucose metabolism to incretin/cAMP action to amplify insulin secretion.
      ,
      • Høy M.
      • Maechler P.
      • Efanov A.M.
      • Wollheim C.B.
      • Berggren P.O.
      • Gromada J.
      Increase in cellular glutamate levels stimulates exocytosis in pancreatic β-cells.
      ,
      • Maechler P.
      • Wollheim C.B.
      Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis.
      ,
      • Rubi B.
      • Ishihara H.
      • Hegardt F.G.
      • Wollheim C.B.
      • Maechler P.
      GAD65-mediated glutamate decarboxylation reduces glucose-stimulated insulin secretion in pancreatic β cells.
      ). The amplifying pathway, formerly referred to as the K-ATP-independent pathway, was uncovered more than two decades ago (
      • Gembal M.
      • Gilon P.
      • Henquin J.C.
      Evidence that glucose can control insulin release independently from its action on ATP-sensitive K+ channels in mouse B cells.
      ). However, its physiological function remains unclear, in particular because it is activated by rather high glucose concentrations. Moreover, mice lacking β-cell GDH and maintained on normal chow diet are asymptomatic, although the secretory response of their β-cells is limited (
      • Carobbio S.
      • Frigerio F.
      • Rubi B.
      • Vetterli L.
      • Bloksgaard M.
      • Gjinovci A.
      • Pournourmohammadi S.
      • Herrera P.L.
      • Reith W.
      • Mandrup S.
      • Maechler P.
      Deletion of glutamate dehydrogenase in β-cells abolishes part of the insulin secretory response not required for glucose homeostasis.
      ).
      A related open question is how efficient a β-cell should be for maintenance of energy homeostasis. Obesity is associated with hyperinsulinemia typically because of insulin resistance (
      • Kasuga M.
      Insulin resistance and pancreatic β cell failure.
      ), which may lead to diabetes in case of subsequent β-cell failure (
      • Prentki M.
      • Nolan C.J.
      Islet β cell failure in type 2 diabetes.
      ). However, mice can be genetically protected against obesity either by the reduction of insulin gene dosage (
      • Mehran A.E.
      • Templeman N.M.
      • Brigidi G.S.
      • Lim G.E.
      • Chu K.Y.
      • Hu X.
      • Botezelli J.D.
      • Asadi A.
      • Hoffman B.G.
      • Kieffer T.J.
      • Bamji S.X.
      • Clee S.M.
      • Johnson J.D.
      Hyperinsulinemia drives diet-induced obesity independently of brain insulin production.
      ,
      • Templeman N.M.
      • Clee S.M.
      • Johnson J.D.
      Suppression of hyperinsulinaemia in growing female mice provides long-term protection against obesity.
      ) or by the ablation of insulin signaling in adipose tissue (
      • Blüher M.
      • Michael M.D.
      • Peroni O.D.
      • Ueki K.
      • Carter N.
      • Kahn B.B.
      • Kahn C.R.
      Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance.
      ). One can postulate that the maximal potential of insulin production by the β-cell might not be necessary under the normal energy homeostatic state, as shown in mice having genetically reduced insulin production (
      • Mehran A.E.
      • Templeman N.M.
      • Brigidi G.S.
      • Lim G.E.
      • Chu K.Y.
      • Hu X.
      • Botezelli J.D.
      • Asadi A.
      • Hoffman B.G.
      • Kieffer T.J.
      • Bamji S.X.
      • Clee S.M.
      • Johnson J.D.
      Hyperinsulinemia drives diet-induced obesity independently of brain insulin production.
      ). Such assumption is also supported by clinical data showing maintenance of glucose tolerance in donors of islets who underwent partial pancreatectomy (
      • Matsumoto S.
      • Okitsu T.
      • Iwanaga Y.
      • Noguchi H.
      • Nagata H.
      • Yonekawa Y.
      • Yamada Y.
      • Fukuda K.
      • Tsukiyama K.
      • Suzuki H.
      • Kawasaki Y.
      • Shimodaira M.
      • Matsuoka K.
      • Shibata T.
      • Kasai Y.
      • et al.
      Insulin independence after living-donor distal pancreatectomy and islet allotransplantation.
      ). However, preservation of normoglycemia, while having half of the full potential for insulin release, might be compromised in conditions requiring increased insulin production, such as obesity-associated insulin resistance or pregnancy (
      • Robertson R.P.
      • Lanz K.J.
      • Sutherland D.E.
      • Seaquist E.R.
      Relationship between diabetes and obesity 9 to 18 years after hemipancreatectomy and transplantation in donors and recipients.
      ). Pharmacologically, inhibition of insulin secretion can be achieved by use of the somatostatin analogue octreotide (
      • Lamberts S.W.
      • van der Lely A.J.
      • de Herder W.W.
      • Hofland L.J.
      Octreotide.
      ) or the non-selective potassium channel opener diazoxide (
      • Shyng S.
      • Ferrigni T.
      • Nichols C.G.
      Regulation of KATP channel activity by diazoxide and MgADP. Distinct functions of the two nucleotide binding folds of the sulfonylurea receptor.
      ). Obese patients who received octreotide for 6 months lost weight compared with placebo (
      • Lustig R.H.
      • Greenway F.
      • Velasquez-Mieyer P.
      • Heimburger D.
      • Schumacher D.
      • Smith D.
      • Smith W.
      • Soler N.
      • Warsi G.
      • Berg W.
      • Maloney J.
      • Benedetto J.
      • Zhu W.
      • Hohneker J.
      A multicenter, randomized, double-blind, placebo-controlled, dose-finding trial of a long-acting formulation of octreotide in promoting weight loss in obese adults with insulin hypersecretion.
      ). In a pilot study conducted on obese subjects, high dose diazoxide treatment over a 6-month period reduced their fasting insulin and fat mass (
      • van Boekel G.
      • Loves S.
      • van Sorge A.
      • Ruinemans-Koerts J.
      • Rijnders T.
      • de Boer H.
      Weight loss in obese men by caloric restriction and high-dose diazoxide-mediated insulin suppression.
      ). Thus, on a background of obesity and hyperinsulinemia, reducing the β-cell efficiency could favorably impact on body weight. Whether in the case of impaired β-cell amplifying pathway a high fat diet prevents obesity or promotes diabetes is unknown.
      Here, we used mice lacking GDH in β-cells and investigated the consequences of genetically limited insulin secretion on energy homeostasis in mice fed a high calorie diet. The results show that inhibition of an amplifying pathway of the secretory response in the β-cells completely protected against diet-induced obesity.

      Discussion

      Previous studies have shown that GDH is necessary for the full development of the secretory response, and the absence of this mitochondrial enzyme sets a limit (∼50%) to maximal insulin release (
      • Carobbio S.
      • Frigerio F.
      • Rubi B.
      • Vetterli L.
      • Bloksgaard M.
      • Gjinovci A.
      • Pournourmohammadi S.
      • Herrera P.L.
      • Reith W.
      • Mandrup S.
      • Maechler P.
      Deletion of glutamate dehydrogenase in β-cells abolishes part of the insulin secretory response not required for glucose homeostasis.
      ). In particular, lack of GDH in the β-cell disrupts an amplifying pathway normally induced by robust stimulation of the secretory response (
      • Vetterli L.
      • Carobbio S.
      • Pournourmohammadi S.
      • Martin-Del-Rio R.
      • Skytt D.M.
      • Waagepetersen H.S.
      • Tamarit-Rodriguez J.
      • Maechler P.
      Delineation of glutamate pathways and secretory responses in pancreatic islets with β-cell specific abrogation of the glutamate dehydrogenase.
      ). Noteworthy, reduced β-cell secretory response is asymptomatic, pending specific metabolic adaptations and under conditions of normo-calorie feeding (
      • Carobbio S.
      • Frigerio F.
      • Rubi B.
      • Vetterli L.
      • Bloksgaard M.
      • Gjinovci A.
      • Pournourmohammadi S.
      • Herrera P.L.
      • Reith W.
      • Mandrup S.
      • Maechler P.
      Deletion of glutamate dehydrogenase in β-cells abolishes part of the insulin secretory response not required for glucose homeostasis.
      ). The fact that β-cell function was limited but not abrogated might explain the observed preservation of normal animal growth. This is the case when mice are fed ad libitum a normal diet not requiring extraordinary signals of abundance in the form of high insulin. However, limiting β-cell secretory response protected against diet-induced obesity. In particular, induction of fat storage in adipocytes of βGlud1−/− mice under HFD diet was prevented, pointing to limited insulin signaling (
      • Stumvoll M.
      • Goldstein B.J.
      • van Haeften T.W.
      Type 2 diabetes: principles of pathogenesis and therapy.
      ). This effect does not rule out other putative contributions, such as central effects or subtle changes in thermogenesis potentially masked by the inherent multifactorial balance of energy expenditure (
      • Virtue S.
      • Even P.
      • Vidal-Puig A.
      Below thermoneutrality, changes in activity do not drive changes in total daily energy expenditure between groups of mice.
      ), although βGlud1−/− mice on the chow diet did not exhibit changes in weight gain.
      Protection against obesity has been reported previously in knock-out mouse models with either lower insulin supply (
      • Mehran A.E.
      • Templeman N.M.
      • Brigidi G.S.
      • Lim G.E.
      • Chu K.Y.
      • Hu X.
      • Botezelli J.D.
      • Asadi A.
      • Hoffman B.G.
      • Kieffer T.J.
      • Bamji S.X.
      • Clee S.M.
      • Johnson J.D.
      Hyperinsulinemia drives diet-induced obesity independently of brain insulin production.
      ,
      • Templeman N.M.
      • Clee S.M.
      • Johnson J.D.
      Suppression of hyperinsulinaemia in growing female mice provides long-term protection against obesity.
      ) or impaired insulin action on peripheral tissues (
      • Um S.H.
      • Frigerio F.
      • Watanabe M.
      • Picard F.
      • Joaquin M.
      • Sticker M.
      • Fumagalli S.
      • Allegrini P.R.
      • Kozma S.C.
      • Auwerx J.
      • Thomas G.
      Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity.
      ,
      • Jones J.R.
      • Barrick C.
      • Kim K.A.
      • Lindner J.
      • Blondeau B.
      • Fujimoto Y.
      • Shiota M.
      • Kesterson R.A.
      • Kahn B.B.
      • Magnuson M.A.
      Deletion of PPARγ in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance.
      ). Mice with adipose tissue-selective insulin receptor knock-out (FIRKO mice) are protected against obesity (
      • Blüher M.
      • Michael M.D.
      • Peroni O.D.
      • Ueki K.
      • Carter N.
      • Kahn B.B.
      • Kahn C.R.
      Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance.
      ). The associated absence of insulin signaling in adipose tissue represses Glut-1 and enhances adiponectin expression (
      • Blüher M.
      • Michael M.D.
      • Peroni O.D.
      • Ueki K.
      • Carter N.
      • Kahn B.B.
      • Kahn C.R.
      Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance.
      ). In the present study, β-cell-selective GDH knock-out mice maintained lower expression of Glut-1 and ERK1 in adipose tissue compared with control obese animals, thereby preventing adipogenesis. Expression of the adipocyte-derived antidiabetic hormone adiponectin (
      • Yamauchi T.
      • Kamon J.
      • Minokoshi Y.
      • Ito Y.
      • Waki H.
      • Uchida S.
      • Yamashita S.
      • Noda M.
      • Kita S.
      • Ueki K.
      • Eto K.
      • Akanuma Y.
      • Froguel P.
      • Foufelle F.
      • Ferre P.
      • et al.
      Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase.
      ) was also preserved in our βGlud1−/− mice, in good agreement with higher insulin sensitivity compared with controls. Our data demonstrate that the primary limitation of the β-cell response recapitulates effects observed downstream on insulin signaling and points to insulin as a key signal governing peripheral tissue adaptation.
      In a previous study (
      • Movassat J.
      • Bailbé D.
      • Lubrano-Berthelier C.
      • Picarel-Blanchot F.
      • Bertin E.
      • Mourot J.
      • Portha B.
      Follow-up of GK rats during prediabetes highlights increased insulin action and fat deposition despite low insulin secretion.
      ), the authors investigated glucose homeostasis in a prediabetes state of Goto-Kakizaki rats, a model of spontaneous type 2 diabetes developing glucose intolerance (
      • Goto Y.
      • Kakizaki M.
      • Masaki N.
      Production of spontaneous diabetic rats by repetition of selective breeding.
      ,
      • Portha B.
      • Serradas P.
      • Bailbé D.
      • Suzuki K.
      • Goto Y.
      • Giroix M.H.
      β-Cell insensitivity to glucose in the GK rat, a spontaneous nonobese model for type II diabetes.
      ). In 3-week-old prediabetic Goto-Kakizaki rats, the authors observed glucose tolerance despite markedly reduced β-cell secretory response upon glucose stimulation (
      • Movassat J.
      • Bailbé D.
      • Lubrano-Berthelier C.
      • Picarel-Blanchot F.
      • Bertin E.
      • Mourot J.
      • Portha B.
      Follow-up of GK rats during prediabetes highlights increased insulin action and fat deposition despite low insulin secretion.
      ). The βGlud1−/− mice exhibited similar adaptation to low β-cell function with preserved glucose homeostasis. Our data are also in agreement with those obtained from mice lacking the G protein-coupled receptor GPR40 activated by free fatty acids and expressed in β-cells. Such GPR40-deficient mice secrete less insulin in response fatty acids and partially maintain glucose homeostasis and insulin sensitivity upon high fat diet (
      • Steneberg P.
      • Rubins N.
      • Bartoov-Shifman R.
      • Walker M.D.
      • Edlund H.
      The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse.
      ). Altogether, these data indicate unexpected efficient adaptation of peripheral tissues to β-cell performance.
      According to the World Health Organization (fact sheet no. 311), at the present time more people worldwide suffer from excessive rather than limited energy supply. Under this new paradigm, it is an intriguing concept whether high β-cell efficiency, acquired through evolution, could participate to obesity predisposition. The pancreatic β-cell has evolved over millions of years toward high performance to fully optimize energy storage during occasional short periods of food abundance to resist starvation periods. In the light of present and previous results, one can speculate that the amplifying pathway in β-cell appeared as a signal of exceptional abundance, induced in conditions of high nutrient supply to optimize storage of energy exceeding immediate requirements by the organism. It is noteworthy that investigators typically study the amplifying pathway in experimental conditions where insulin release is evoked by the highest physiological glucose concentrations. Such an experimental paradigm might not reflect ordinary requirement of β-cell function in individuals with appropriate and regular nutrient intake.
      We previously reported that βGlud1−/− mice, exhibiting half of the maximal insulin secretion amplitude, perform similar energy homoeostasis and nutrient storage as controls, pending access to balanced carbohydrate rich diet (
      • Carobbio S.
      • Frigerio F.
      • Rubi B.
      • Vetterli L.
      • Bloksgaard M.
      • Gjinovci A.
      • Pournourmohammadi S.
      • Herrera P.L.
      • Reith W.
      • Mandrup S.
      • Maechler P.
      Deletion of glutamate dehydrogenase in β-cells abolishes part of the insulin secretory response not required for glucose homeostasis.
      ). On a high calorie diet, limitation of excessive fat deposit in adipose tissues protected knock-out mice from high fat diet-induced obesity and the accompanying insulin resistance. At the clinical level, a few studies have been conducted in obese subjects using diazoxide to inhibit insulin secretion from the β-cell. Short term treatments showed contradictory results with either no change in body weight (
      • Alemzadeh R.
      • Langley G.
      • Upchurch L.
      • Smith P.
      • Slonim A.E.
      Beneficial effect of diazoxide in obese hyperinsulinemic adults.
      ) or anti-obesity effect in hyperinsulinemic obese adults (
      • Due A.
      • Flint A.
      • Eriksen G.
      • Møller B.
      • Raben A.
      • Hansen J.B.
      • Astrup A.
      No effect of inhibition of insulin secretion by diazoxide on weight loss in hyperinsulinaemic obese subjects during an 8-week weight-loss diet.
      ). A 6-month diazoxide treatment of obese hyperinsulinemic men, combined with moderate caloric restriction, resulted in lower fasting insulin levels associated with significant weight loss, in particular of the fat mass (
      • van Boekel G.
      • Loves S.
      • van Sorge A.
      • Ruinemans-Koerts J.
      • Rijnders T.
      • de Boer H.
      Weight loss in obese men by caloric restriction and high-dose diazoxide-mediated insulin suppression.
      ). Diazoxide induces hyperglycemia, which is not observed in βGlud1−/− mice possibly because, to some extent, their β-cells remained sensitive to glucose. In our study, limitation of the β-cell secretory response prior to obesity induction completely prevented overweight gain, whereas limiting insulin release in obese mice had marginal effects on body weight while preserving glucose homeostasis. Taken together, pilot clinical studies, as well as present mechanistic data, call for better understanding of the contribution of insulin release by the β-cell toward development of obesity, opening new avenues for the prevention of type 2 diabetes.

      Author Contributions

      L. V., S. C., F. F., and M. K. contributed to the study design, performed experiments, acquired and analyzed data, and contributed to the writing of the manuscript. P. M. designed the study, analyzed data, and wrote the manuscript. All authors critically reviewed and approved the manuscript.

      Acknowledgments

      We thank Gaelle Chaffard and Clarissa Bartley for expert technical assistance, Christelle Veyrat-Durebex for calorimetric measurements, and Thierry Brun for careful reading of the manuscript (Geneva).

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