Liver glucose metabolism plays a central role in glucose homeostasis and may also regulate feeding and energy expenditure. Here we assessed the impact of glucose transporter 2 (
Pascal Seyer, David Vallois, Carole Poitry-Yamate, Frédéric Schütz, Salima Metref, David Tarussio, Pierre Maechler, Bart Staels, Bernard Lanz, Rolf Grueter, Julie Decaris, Scott Turner, Anabela da Costa, Frédéric Preitner, Kaori Minehira, Marc Foretz, Bernard Thorens
When a person consumes ethanol, the body quickly begins to convert it to acetic acid, which circulates in the blood and can serve as a source of energy for the brain and other organs. This study used 13C magnetic resonance spectroscopy to test whether chronic heavy drinking is associated with greater brain uptake and oxidation of acetic acid, providing a potential metabolic reward or adenosinergic effect as a consequence of drinking. Seven heavy drinkers, who regularly consumed at least 8 drinks per week and at least 4 drinks per day at least once per week, and 7 light drinkers, who consumed fewer than 2 drinks per week were recruited. The subjects were administered [2-13C]acetate for 2 hours and scanned throughout that time with magnetic resonance spectroscopy of the brain to observe natural 13C abundance of N-acetylaspartate (NAA) and the appearance of 13C-labeled glutamate, glutamine, and acetate. Heavy drinkers had approximately 2-fold more brain acetate relative to blood and twice as much labeled glutamate and glutamine. The results show that acetate transport and oxidation are faster in heavy drinkers compared with that in light drinkers. Our finding suggests that a new therapeutic approach to supply acetate during alcohol detoxification may be beneficial.
Lihong Jiang, Barbara Irene Gulanski, Henk M. De Feyter, Stuart A. Weinzimer, Brian Pittman, Elizabeth Guidone, Julia Koretski, Susan Harman, Ismene L. Petrakis, John H. Krystal, Graeme F. Mason
Exogenous dietary fat can induce obesity and promote diabetes, but endogenous fat production is not thought to affect skeletal muscle insulin resistance, an antecedent of metabolic disease. Unexpectedly, the lipogenic enzyme fatty acid synthase (FAS) was increased in the skeletal muscle of mice with diet-induced obesity and insulin resistance. Skeletal muscle–specific inactivation of FAS protected mice from insulin resistance without altering adiposity, specific inflammatory mediators of insulin signaling, or skeletal muscle levels of diacylglycerol or ceramide. Increased insulin sensitivity despite high-fat feeding was driven by activation of AMPK without affecting AMP content or the AMP/ATP ratio in resting skeletal muscle. AMPK was induced by elevated cytosolic calcium caused by impaired sarco/endoplasmic reticulum calcium ATPase (SERCA) activity due to altered phospholipid composition of the sarcoplasmic reticulum (SR), but came at the expense of decreased muscle strength. Thus, inhibition of skeletal muscle FAS prevents obesity-associated diabetes in mice, but also causes muscle weakness, which suggests that mammals have retained the capacity for lipogenesis in muscle to preserve physical performance in the setting of disrupted metabolic homeostasis.
Katsuhiko Funai, Haowei Song, Li Yin, Irfan J. Lodhi, Xiaochao Wei, Jun Yoshino, Trey Coleman, Clay F. Semenkovich
Patients with type 1 diabetes mellitus (T1DM) experience, on average, 2 to 3 hypoglycemic episodes per week. This study investigated the effect of hypoglycemia on cerebral glucose metabolism in patients with uncomplicated T1DM. For this purpose, hyperinsulinemic euglycemic and hypoglycemic glucose clamps were performed on separate days, using [1-13C]glucose infusion to increase plasma 13C enrichment. In vivo brain 13C magnetic resonance spectroscopy was used to measure the time course of 13C label incorporation into different metabolites and to calculate the tricarboxylic acid cycle flux (VTCA) by a one-compartment metabolic model. We found that cerebral glucose metabolism, as reflected by the VTCA, was not significantly different comparing euglycemic and hypoglycemic conditions in patients with T1DM. However, the VTCA was inversely related to the HbA1C and was, under hypoglycemic conditions, approximately 45% higher than that in a previously investigated group of healthy subjects. These data suggest that the brains of patients with T1DM are better able to endure moderate hypoglycemia than those of subjects without diabetes.
Kim C.C. van de Ven, Cees J. Tack, Arend Heerschap, Marinette van der Graaf, Bastiaan E. de Galan
The scaffold protein p62 (sequestosome 1; SQSTM1) is an emerging key molecular link among the metabolic, immune, and proliferative processes of the cell. Here, we report that adipocyte-specific, but not CNS-, liver-, muscle-, or myeloid-specific
Timo D. Müller, Sang Jun Lee, Martin Jastroch, Dhiraj Kabra, Kerstin Stemmer, Michaela Aichler, Bill Abplanalp, Gayathri Ananthakrishnan, Nakul Bhardwaj, Sheila Collins, Senad Divanovic, Max Endele, Brian Finan, Yuanqing Gao, Kirk M. Habegger, Jazzmin Hembree, Kristy M. Heppner, Susanna Hofmann, Jenna Holland, Daniela Küchler, Maria Kutschke, Radha Krishna, Maarit Lehti, Rebecca Oelkrug, Nickki Ottaway, Diego Perez-Tilve, Christine Raver, Axel K. Walch, Sonja C. Schriever, John Speakman, Yu-Hua Tseng, Maria Diaz-Meco, Paul T. Pfluger, Jorge Moscat, Matthias H. Tschöp
Postprandially, the liver experiences an extensive metabolic reprogramming that is required for the switch from glucose production to glucose assimilation. Upon refeeding, the unfolded protein response (UPR) is rapidly, though only transiently, activated. Activation of the UPR results in a cessation of protein translation, increased chaperone expression, and increased ER-mediated protein degradation, but it is not clear how the UPR is involved in the postprandial switch to alternate fuel sources. Activation of the inositol-requiring enzyme 1 (IRE1) branch of the UPR signaling pathway triggers expression of the transcription factor Xbp1s. Using a mouse model with liver-specific inducible Xbp1s expression, we demonstrate that Xbp1s is sufficient to provoke a metabolic switch characteristic of the postprandial state, even in the absence of caloric influx. Mechanistically, we identified UDP-galactose-4-epimerase (GalE) as a direct transcriptional target of Xbp1s and as the key mediator of this effect. Our results provide evidence that the Xbp1s/GalE pathway functions as a novel regulatory nexus connecting the UPR to the characteristic postprandial metabolic changes in hepatocytes.
Yingfeng Deng, Zhao V. Wang, Caroline Tao, Ningguo Gao, William L. Holland, Anwarul Ferdous, Joyce J. Repa, Guosheng Liang, Jin Ye, Mark A. Lehrman, Joseph A. Hill, Jay D. Horton, Philipp E. Scherer
Brown adipose tissue (BAT) is known to function in the dissipation of chemical energy in response to cold or excess feeding, and also has the capacity to modulate energy balance. To test the hypothesis that BAT is fundamental to the regulation of glucose homeostasis, we transplanted BAT from male donor mice into the visceral cavity of age- and sex-matched recipient mice. By 8–12 weeks following transplantation, recipient mice had improved glucose tolerance, increased insulin sensitivity, lower body weight, decreased fat mass, and a complete reversal of high-fat diet–induced insulin resistance. Increasing the quantity of BAT transplanted into recipient mice further improved the metabolic effects of transplantation. BAT transplantation increased insulin-stimulated glucose uptake in vivo into endogenous BAT, white adipose tissue (WAT), and heart muscle but, surprisingly, not skeletal muscle. The improved metabolic profile was lost when the BAT used for transplantation was obtained from Il6–knockout mice, demonstrating that BAT-derived IL-6 is required for the profound effects of BAT transplantation on glucose homeostasis and insulin sensitivity. These findings reveal a previously under-appreciated role for BAT in glucose metabolism.
Kristin I. Stanford, Roeland J.W. Middelbeek, Kristy L. Townsend, Ding An, Eva B. Nygaard, Kristen M. Hitchcox, Kathleen R. Markan, Kazuhiro Nakano, Michael F. Hirshman, Yu-Hua Tseng, Laurie J. Goodyear
Bariatric surgery in obese patients is a highly effective method of preventing or resolving type 2 diabetes mellitus (T2DM); however, the remission rate is not the same among different surgical procedures. We compared the effects of 20% weight loss induced by laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass (RYGB) surgery on the metabolic response to a mixed meal, insulin sensitivity, and β cell function in nondiabetic obese adults. The metabolic response to meal ingestion was markedly different after RYGB than after LAGB surgery, manifested by rapid delivery of ingested glucose into the systemic circulation, by an increase in the dynamic insulin secretion rate, and by large, early postprandial increases in plasma glucose, insulin, and glucagon-like peptide–1 concentrations in the RYGB group. However, the improvement in oral glucose tolerance, insulin sensitivity, and overall β cell function after weight loss were not different between surgical groups. Additionally, both surgical procedures resulted in a similar decrease in adipose tissue markers of inflammation. We conclude that marked weight loss itself is primarily responsible for the therapeutic effects of RYGB and LAGB on insulin sensitivity, β cell function, and oral glucose tolerance in nondiabetic obese adults.
David Bradley, Caterina Conte, Bettina Mittendorfer, J. Christopher Eagon, J. Esteban Varela, Elisa Fabbrini, Amalia Gastaldelli, Kari T. Chambers, Xiong Su, Adewole Okunade, Bruce W. Patterson, Samuel Klein
Src homology 2 B adapter protein 1 (SH2B1) modulates signaling by a variety of ligands that bind to receptor tyrosine kinases or JAK-associated cytokine receptors, including leptin, insulin, growth hormone (GH), and nerve growth factor (NGF). Targeted deletion of Sh2b1 in mice results in increased food intake, obesity, and insulin resistance, with an intermediate phenotype seen in heterozygous null mice on a high-fat diet. We identified SH2B1 loss-of-function mutations in a large cohort of patients with severe early-onset obesity. Mutation carriers exhibited hyperphagia, childhood-onset obesity, disproportionate insulin resistance, and reduced final height as adults. Unexpectedly, mutation carriers exhibited a spectrum of behavioral abnormalities that were not reported in controls, including social isolation and aggression. We conclude that SH2B1 plays a critical role in the control of human food intake and body weight and is implicated in maladaptive human behavior.
Michael E. Doche, Elena G. Bochukova, Hsiao-Wen Su, Laura R. Pearce, Julia M. Keogh, Elana Henning, Joel M. Cline, Anne Dale, Tim Cheetham, Inês Barroso, Lawrence S. Argetsinger, Stephen O’Rahilly, Liangyou Rui, Christin Carter-Su, I. Sadaf Farooqi
PPARβ/δ protects against obesity by reducing dyslipidemia and insulin resistance via effects in muscle, adipose tissue, and liver. However, its function in pancreas remains ill defined. To gain insight into its hypothesized role in β cell function, we specifically deleted Pparb/d in the epithelial compartment of the mouse pancreas. Mutant animals presented increased numbers of islets and, more importantly, enhanced insulin secretion, causing hyperinsulinemia. Gene expression profiling of pancreatic β cells indicated a broad repressive function of PPARβ/δ affecting the vesicular and granular compartment as well as the actin cytoskeleton. Analyses of insulin release from isolated PPARβ/δ-deficient islets revealed an accelerated second phase of glucose-stimulated insulin secretion. These effects in PPARβ/δ-deficient islets correlated with increased filamentous actin (F-actin) disassembly and an elevation in protein kinase D activity that altered Golgi organization. Taken together, these results provide evidence for a repressive role for PPARβ/δ in β cell mass and insulin exocytosis, and shed a new light on PPARβ/δ metabolic action.
José Iglesias, Sebastian Barg, David Vallois, Shawon Lahiri, Catherine Roger, Akadiri Yessoufou, Sylvain Pradevand, Angela McDonald, Claire Bonal, Frank Reimann, Fiona Gribble, Marie-Bernard Debril, Daniel Metzger, Pierre Chambon, Pedro Herrera, Guy A. Rutter, Marc Prentki, Bernard Thorens, Walter Wahli