Metabolism
Abstract
White adipose tissue (WAT) can dynamically expand and remodel through adipocyte hypertrophy and hyperplasia. The relative contribution of these 2 mechanisms to WAT expansion is a critical determinant of WAT function and dysfunction in obesity. However, little is known about the signaling systems that determine the mechanisms of WAT expansion. Here, we show that the GPCR LPA4 selectively activates Gα12/13 proteins in adipocytes and limits continuous remodeling and healthy expansion of WAT. LPA4-KO mice showed enhanced expression of mitochondrial and adipogenesis genes and reduced levels of inhibitory phosphorylation of PPARγ in WAT, along with increased production of adiponectin. Furthermore, LPA4-KO mice showed metabolically healthy obese phenotypes in a diet-induced obesity model, with continuous WAT expansion, as well as protection from WAT inflammation, hepatosteatosis, and insulin resistance. These findings unravel a potentially new signaling system that underlies WAT plasticity and expandability, providing a promising therapeutic approach for obesity-related metabolic disorders.
Authors
Keisuke Yanagida, Hidemitsu Igarashi, Daisuke Yasuda, Daiki Kobayashi, Takayo Ohto-Nakanishi, Noriyuki Akahoshi, Atsushi Sekiba, Tsudoi Toyoda, Tomoko Ishijima, Yuji Nakai, Nobuhiro Shojima, Naoto Kubota, Keiko Abe, Takashi Kadowaki, Satoshi Ishii, Takao Shimizu
Abstract
BACKGROUND. Excessive insulin secretion may lead to glucose dysregulation. Our aim was to identify primary (independent of insulin resistance) insulin hypersecretion in subjects with normal glucose tolerance and its role in the progression of dysglycemia. METHODS. In 1,168 adults, insulin secretion rate (ISR) and β cell function were estimated by C-peptide modeling during an oral glucose tolerance test (OGTT) and an i.v. glucose tolerance test. Whole-body insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp. After regressing ISR on insulin sensitivity, subjects in the upper tertile of the distribution of residuals were defined as primary hypersecretors. This approach was applied to a biethnic cohort of 182 obese adolescents, who received an OGTT, a hyperglycemic, and a euglycemic clamp. RESULTS. Adult hypersecretors showed older age, more familial diabetes, sedentary lifestyle, increased fat mass, and worse lipid profile compared with the rest of the cohort, despite virtually identical BMI and insulin sensitivity. Insulin secretion was increased by 53% due to enhanced (+23%) β cell glucose sensitivity. Despite the resulting hyperinsulinemia, glucose tolerance was worse in hypersecretors among both adults and adolescents, coupled with higher indices of liver insulin resistance and increased availability of gluconeogenic substrates. At the 3-year follow-up, adult hypersecretors had increased incidence of impaired glucose tolerance/type 2 diabetes. CONCLUSION. Primary insulin hypersecretion, independent of insulin resistance, is associated with a worse clinical and metabolic phenotype in adults and adolescents and predicts deterioration of glucose control over time. FUNDING. The relationship between insulin sensitivity and cardiovascular disease (RISC) Study was partly supported by EU grant QLG1-CT-2001-01252.
Authors
Domenico Tricò, Andrea Natali, Silva Arslanian, Andrea Mari, Ele Ferrannini
Abstract
Sialic acids are important components of glycoproteins and glycolipids essential for cellular communication, infection, and metastasis. The importance of sialic acid biosynthesis in human physiology is well illustrated by the severe metabolic disorders in this pathway. However, the biological role of sialic acid catabolism in humans remains unclear. Here, we present evidence that sialic acid catabolism is important for heart and skeletal muscle function and development in humans and zebrafish. In two siblings, presenting with sialuria, exercise intolerance/muscle wasting, and cardiac symptoms in the brother, compound heterozygous mutations [chr1:182775324C>T (c.187C>T; p.Arg63Cys) and chr1:182772897A>G (c.133A>G; p.Asn45Asp)] were found in the N-acetylneuraminate pyruvate lyase gene (NPL). In vitro, NPL activity and sialic acid catabolism were affected, with a cell-type-specific reduction of N-acetyl mannosamine (ManNAc). A knockdown of NPL in zebrafish resulted in severe skeletal myopathy and cardiac edema, mimicking the human phenotype. The phenotype was rescued by expression of wild-type human NPL but not by the p.Arg63Cys or p.Asn45Asp mutants. Importantly, the myopathy phenotype in zebrafish embryos was rescued by treatment with the catabolic products of NPL: N-acetyl glucosamine (GlcNAc) and ManNAc; the latter also rescuing the cardiac phenotype. In conclusion, we provide the first report to our knowledge of a human defect in sialic acid catabolism, which implicates an important role of the sialic acid catabolic pathway in mammalian muscle physiology, and suggests opportunities for monosaccharide replacement therapy in human patients.
Authors
Xiao-Yan Wen, Maja Tarailo-Graovac, Koroboshka Brand-Arzamendi, Anke Willems, Bojana Rakic, Karin Huijben, Afitz Da Silva, Xuefang Pan, Suzan El-Rass, Robin Ng, Katheryn Selby, Anju Mary Philip, Junghwa Yun, X. Cynthia Ye, Colin J. Ross, Anna M. Lehman, Fokje Zijlstra, N. Abu Bakar, Britt Drögemöller, Jacqueline Moreland, Wyeth W. Wasserman, Hilary Vallance, Monique van Scherpenzeel, Farhad Karbassi, Martin Hoskings, Udo Engelke, Arjan de Brouwer, Ron A. Wevers, Alexey V. Pshezhetsky, Clara D.M. van Karnebeek, Dirk J. Lefeber
Abstract
Methylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA in acute and chronic settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut–/–;TgINS-MCK-Mut mice accurately replicate the hepatorenal mitochondriopathy and growth failure seen in severely affected patients and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and an aberrant fasting response when compared with controls. A key metabolic regulator, Fgf21, emerged as a significantly dysregulated transcript in mice and was subsequently studied in a large patient cohort. The concentration of plasma FGF21 in MMA patients correlated with disease subtype, growth indices, and markers of mitochondrial dysfunction but was not affected by renal disease. Restoration of liver Mut activity, by transgenesis and liver-directed gene therapy in mice or liver transplantation in patients, drastically reduced plasma FGF21 and was associated with improved outcomes. Our studies identify mitocellular hormesis as a hepatic adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker.
Authors
Irini Manoli, Justin R. Sysol, Madeline W. Epping, Lina Li, Cindy Wang, Jennifer L. Sloan, Alexandra Pass, Jack Gagné, Yiouli P. Ktena, Lingli Li, Niraj S. Trivedi, Bazoumana Ouattara, Patricia M. Zerfas, Victoria Hoffmann, Mones Abu-Asab, Maria G. Tsokos, David E. Kleiner, Caterina Garone, Kristina Cusmano-Ozog, Gregory M. Enns, Hilary J. Vernon, Hans C. Andersson, Stephanie Grunewald, Abdel G. Elkahloun, Christiane L. Girard, Jurgen Schnermann, Salvatore DiMauro, Eva Andres-Mateos, Luk H. Vandenberghe, Randy J. Chandler, Charles P. Venditti
Abstract
BACKGROUND. Metformin reduces plasma glucose and has been shown to increase glucagon-like peptide 1 (GLP-1) secretion. Whether this is a direct action of metformin on GLP-1 release, and whether some of the glucose-lowering effect of metformin occurs due to GLP-1 release, is unknown. The current study investigated metformin-induced GLP-1 secretion and its contribution to the overall glucose-lowering effect of metformin and underlying mechanisms in patients with type 2 diabetes. METHODS. Twelve patients with type 2 diabetes were included in this placebo-controlled, double-blinded study. On 4 separate days, the patients received metformin (1,500 mg) or placebo suspended in a liquid meal, with subsequent i.v. infusion of the GLP-1 receptor antagonist exendin9-39 (Ex9-39) or saline. During 240 minutes, blood was sampled. The direct effect of metformin on GLP-1 secretion was tested ex vivo in human ileal and colonic tissue with and without dorsomorphin-induced inhibiting of the AMPK activity. RESULTS. Metformin increased postprandial GLP-1 secretion compared with placebo (P = 0.014), and the postprandial glucose excursions were significantly smaller after metformin + saline compared with metformin + Ex9-39 (P = 0.004). Ex vivo metformin acutely increased GLP-1 secretion (colonic tissue, P < 0.01; ileal tissue, P < 0.05), but the effect was abolished by inhibition of AMPK activity. CONCLUSIONS. Metformin has a direct and AMPK-dependent effect on GLP-1–secreting L cells and increases postprandial GLP-1 secretion, which seems to contribute to metformin’s glucose-lowering effect and mode of action. TRIAL REGISTRATION. NCT02050074 (https://clinicaltrials.gov/ct2/show/NCT02050074). FUNDING. This study received grants from the A.P. Møller Foundation, the Novo Nordisk Foundation, the Danish Medical Association research grant, the Australian Research Council, the National Health and Medical Research Council, and Pfizer Inc.
Authors
Emilie Bahne, Emily W. L. Sun, Richard L. Young, Morten Hansen, David P. Sonne, Jakob S. Hansen, Ulrich Rohde, Alice P. Liou, Margaret L. Jackson, Dayan de Fontgalland, Philippa Rabbitt, Paul Hollington, Luigi Sposato, Steven Due, David A. Wattchow, Jens F. Rehfeld, Jens J. Holst, Damien J. Keating, Tina Vilsbøll, Filip K. Knop
Abstract
Obesity is characterized by accumulation of adipose tissue and is one the most important risk factors in the development of insulin resistance. Carbon monoxide–releasing (CO-releasing) molecules (CO-RMs) have been reported to improve the metabolic profile of obese mice, but the underlying mechanism remains poorly defined. Here, we show that oral administration of CORM-401 to obese mice fed a high-fat diet (HFD) resulted in a significant reduction in body weight gain, accompanied by a marked improvement in glucose homeostasis. We further unmasked an action we believe to be novel, by which CO accumulates in visceral adipose tissue and uncouples mitochondrial respiration in adipocytes, ultimately leading to a concomitant switch toward glycolysis. This was accompanied by enhanced systemic and adipose tissue insulin sensitivity, as indicated by a lower blood glucose and increased Akt phosphorylation. Our findings indicate that the transient uncoupling activity of CO elicited by repetitive administration of CORM-401 is associated with lower weight gain and increased insulin sensitivity during HFD. Thus, prototypic compounds that release CO could be investigated for developing promising insulin-sensitizing agents.
Authors
Laura Braud, Maria Pini, Lucie Muchova, Sylvie Manin, Hiroaki Kitagishi, Daigo Sawaki, Gabor Czibik, Julien Ternacle, Geneviève Derumeaux, Roberta Foresti, Roberto Motterlini
Abstract
IQ motif–containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffolding protein that integrates multiple cellular processes, including motility, adhesion, and proliferation, but its role in metabolism is unknown. Here, we show that IQGAP1 is induced upon fasting and regulates β-oxidation of fatty acids and synthesis of ketone bodies in the liver. IQGAP1-null (Iqgap1–/–) mice exhibit reduced hepatic PPARα transcriptional activity, as evidenced during fasting, after ketogenic diet, and upon pharmacological activation. Conversely, we found that the activity of fed-state sensor mTORC1 is enhanced in Iqgap1–/– livers, but acute inhibition of mTOR in Iqgap1–/– mice was unable to rescue the defect in ketone body synthesis. However, reexpressing IQGAP1 in the livers of Iqgap1–/– mice was sufficient to promote ketone body synthesis, increase PPARα signaling, and suppress mTORC1 activity. Taken together, we uncover what we believe to be a previously unidentified role for IQGAP1 in regulating PPARα activity and ketogenesis.
Authors
Hanna L. Erickson, Sayeepriyadarshini Anakk
Abstract
The most severe manifestation of peripheral arterial disease (PAD) is critical limb ischemia (CLI). CLI patients suffer high rates of amputation and mortality; accordingly, there remains a clear need both to better understand CLI and to develop more effective treatments. Gastrocnemius muscle was obtained from 32 older (51–84 years) non-PAD controls, 27 claudicating PAD patients (ankle-brachial index [ABI] 0.65 ± 0.21 SD), and 19 CLI patients (ABI 0.35 ± 0.30 SD) for whole transcriptome sequencing and comprehensive mitochondrial phenotyping. Comparable permeabilized myofiber mitochondrial function was paralleled by both similar mitochondrial content and related mRNA expression profiles in non-PAD control and claudicating patient tissues. Tissues from CLI patients, despite being histologically intact and harboring equivalent mitochondrial content, presented a unique bioenergetic signature. This signature was defined by deficits in permeabilized myofiber mitochondrial function and a unique pattern of both nuclear and mitochondrial encoded gene suppression. Moreover, isolated muscle progenitor cells retained both mitochondrial functional deficits and gene suppression observed in the tissue. These findings indicate that muscle tissues from claudicating patients and non-PAD controls were similar in both their bioenergetics profile and mitochondrial phenotypes. In contrast, CLI patient limb skeletal muscles harbor a unique skeletal muscle mitochondriopathy that represents a potentially novel therapeutic site for intervention.
Authors
Terence E. Ryan, Dean J. Yamaguchi, Cameron A. Schmidt, Tonya N. Zeczycki, Saame Raza Shaikh, Patricia Brophy, Thomas D. Green, Michael D. Tarpey, Reema Karnekar, Emma J. Goldberg, Genevieve C. Sparagna, Maria J. Torres, Brian H. Annex, P. Darrell Neufer, Espen E. Spangenburg, Joseph M. McClung
Abstract
Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Dietary interventions based on protein restriction (PR) reduce circulating triglycerides (TGs), but underlying mechanisms and clinical relevance remain unclear. Here, we show that 1 week of a protein-free diet without enforced calorie restriction significantly lowered circulating TGs in both lean and diet-induced obese mice. Mechanistically, the TG-lowering effect of PR was due, in part, to changes in very low–density lipoprotein (VLDL) metabolism both in liver and peripheral tissues. In the periphery, PR stimulated VLDL-TG consumption by increasing VLDL-bound APOA5 expression and promoting VLDL-TG hydrolysis and clearance from circulation. The PR-mediated increase in Apoa5 expression was controlled by the transcription factor CREBH, which coordinately regulated hepatic expression of fatty acid oxidation–related genes, including Fgf21 and Ppara. The CREBH-APOA5 axis activation upon PR was intact in mice lacking the GCN2-dependent amino acid–sensing arm of the integrated stress response. However, constitutive hepatic activation of the amino acid–responsive kinase mTORC1 compromised CREBH activation, leading to blunted APOA5 expression and PR-recalcitrant hypertriglyceridemia. PR also contributed to hypotriglyceridemia by reducing the rate of VLDL-TG secretion, independently of activation of the CREBH-APOA5 axis. Finally, a randomized controlled clinical trial revealed that 4–6 weeks of reduced protein intake (7%–9% of calories) decreased VLDL particle number, increased VLDL-bound APOA5 expression, and lowered plasma TGs, consistent with mechanistic conservation of PR-mediated hypotriglyceridemia in humans with translational potential as a nutraceutical intervention for dyslipidemia.
Authors
J. Humberto Treviño-Villarreal, Justin S. Reynolds, Alexander Bartelt, P. Kent Langston, Michael R. MacArthur, Alessandro Arduini, Valeria Tosti, Nicola Veronese, Beatrice Bertozzi, Lear E. Brace, Pedro Mejia, Kaspar Trocha, Gustavo S. Kajitani, Alban Longchamp, Eylul Harputlugil, Rose Gathungu, Susan S. Bird, Arnold D. Bullock, Robert S. Figenshau, Gerald L. Andriole, Andrew Thompson, Jöerg Heeren, C. Keith Ozaki, Bruce S. Kristal, Luigi Fontana, James R. Mitchell
Abstract
BACKGROUND. In inflammatory blood vessel diseases, macrophages represent a key component of the vascular infiltrates and are responsible for tissue injury and wall remodeling. METHODS. To examine whether inflammatory macrophages in the vessel wall display a single distinctive effector program, we compared functional profiles in patients with either coronary artery disease (CAD) or giant cell arteritis (GCA). RESULTS. Unexpectedly, monocyte-derived macrophages from the 2 patient cohorts displayed disease-specific signatures and differed fundamentally in metabolic fitness. Macrophages from CAD patients were high producers for T cell chemoattractants (CXCL9, CXCL10), the cytokines IL-1β and IL-6, and the immunoinhibitory ligand PD-L1. In contrast, macrophages from GCA patients upregulated production of T cell chemoattractants (CXCL9, CXCL10) but not IL-1β and IL-6, and were distinctly low for PD-L1 expression. Notably, disease-specific effector profiles were already identifiable in circulating monocytes. The chemokinehicytokinehiPD-L1hi signature in CAD macrophages was sustained by excess uptake and breakdown of glucose, placing metabolic control upstream of inflammatory function. CONCLUSIONS. We conclude that monocytes and macrophages contribute to vascular inflammation in a disease-specific and discernible pattern, have choices to commit to different functional trajectories, are dependent on glucose availability in their immediate microenvironment, and possess memory in their lineage commitment. FUNDING. Supported by the NIH (R01 AR042527, R01 HL117913, R01 AI108906, P01 HL129941, R01 AI108891, R01 AG045779 U19 AI057266, R01 AI129191), I01 BX001669, and the Cahill Discovery Fund.
Authors
Ryu Watanabe, Marc Hilhorst, Hui Zhang, Markus Zeisbrich, Gerald J. Berry, Barbara B. Wallis, David G. Harrison, John C. Giacomini, Jörg J. Goronzy, Cornelia M. Weyand
No posts were found with this tag.
