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Targeted Disruption of the SUCNR1 Metabolic Receptor Leads to Dichotomous Effects on Obesity

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Targeted Disruption of the SUCNR1 Metabolic Receptor Leads to Dichotomous Effects on Obesity 1154 Diabetes Volume 64, April 2015 Kenneth J. McCreath,1 Sandra Espada,1 Beatriz G. Gálvez,1 Marina Benito,2,3 Antonio de Molina,4 Pilar Sepúlveda,5 and Ana M. Cervera1,5 Targeted Disruption of the SUCNR1 Metabolic Receptor Leads to Dichotomous Effects on Obesity Diabetes 2015;64:1154–1167 | DOI: 10.2337/db14-0346 A number of metabolites have signaling properties by G-protein–coupled receptors (GPCRs) constitute the major acting through G-protein–coupled receptors. Succinate, and most diverse group of membrane receptors in a Krebs cycle intermediate, increases after dysregu- eukaryotes (1). Found in the plasma membrane, these lated energy metabolism and can bind to its cognate receptors are tasked with the recognition and transmis- receptor succinate receptor 1 (Sucnr1, or GPR91) to ac- sion of messages from the external environment. An ever- tivate downstream signaling pathways. We show that increasing number of GPCRs are now being identified as Sucnr1 is highly expressed in the white adipose tissue receptors for metabolites or energy substrates (2), (WAT) compartment of mice and regulates adipose expanding the repertoire of biological targets to diseases 2/2 mass and glucose homeostasis. Sucnr1 mice were associated with the metabolic syndrome, including hyper- generated, and weight gain was monitored under basal tension and type 2 diabetes (3). Metabolites such as lac- and nutritional stress (high-fat diet [HFD]) conditions. tate (4), ketone bodies (5), and a-ketoglutarate (6), 2/2 METABOLISM On chow diet, Sucnr1 mice had increased energy known primarily to serve functions distinct to signaling, expenditure, were lean with a smaller WAT compart- have been shown to act as ligands for GPCRs. Represen- ment, and had improved glucose buffering. Lipolysis tative of this new class of receptor is Gpr91, a receptor for measurements revealed that Sucnr12/2 mice were re- the Krebs cycle intermediate succinate, now termed leased from succinate-induced inhibition of lipolysis, Sucnr1 for succinate receptor (7). The Krebs, or citric demonstrating a function of Sucnr1 in adipose tissue. acid, cycle occurs at the junction between glycolysis and Sucnr1 deletion also protected mice from obesity on oxidative phosphorylation (8) and is a key component of HFD, but only during the initial period; at later stages, aerobic metabolism by providing reducing equivalents for body weight of HFD-fed Sucnr12/2 mice was almost the electron transport chain. Interestingly, succinate has comparable with wild-type (WT) mice, but WAT content been known for many years to increase in tissues during was greater. Also, these mice became progressively hypoxia (9–11) and may act as a surrogate marker for hyperglycemic and failed to secrete insulin, although reduced oxygenation. Accordingly, Sucnr1 may be acti- pancreas architecture was similar to WT mice. These vated in times of hypoxic stress such as ischemic injury findings suggest that Sucnr1 is a sensor for dietary in liver (12) or retina (13) or during cardiomyocyte crisis energy and raise the interesting possibility that proto- (14). Moreover, dysregulated metabolism, akin to diabetes cols to modulate Sucnr1 might have therapeutic utility or the metabolic syndrome, also has the potential to in- in the setting of obesity. crease peripheral blood concentrations of succinate to 1Department of Cardiovascular Development and Repair, Fundación Centro Corresponding author: Ana M. Cervera, [email protected] or amcerveraz@ Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain gmail.com. 2 Advanced Imaging Unit, Department of Atherothrombosis, Imaging, and Epidemi- Received 28 February 2014 and accepted 14 October 2014. ology, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, This article contains Supplementary Data online at http://diabetes Madrid, Spain .diabetesjournals.org/lookup/suppl/doi:10.2337/db14-0346/-/DC1. 3CIBER de Enfermedades Respiratorias, Madrid, Spain 4Comparative Medicine Unit, Fundación Centro Nacional de Investigaciones Cardio- © 2015 by the American Diabetes Association. Readers may use this article as vasculares Carlos III, Madrid, Spain long as the work is properly cited, the use is educational and not for profit, and 5Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación the work is not altered. Sanitaria La Fe, Valencia, Spain diabetes.diabetesjournals.org McCreath and Associates 1155 levels where activation of the Sucnr1 receptor will occur with genomic DNA extracted from tail biopsies using the (15,16). Indeed, the low levels (;2–80 mmol/L) of succi- REDExtract-N-Amp Tissue PCR kit (Sigma-Aldrich, Saint nate found in blood plasma (15–18), in comparison with Louis, MO). Genotyping primers were primer 1, 59-ACTA that required for activation (in the region of 180 mmol/L TAAGCATCACTTCACCACTTCC-39; primer 2, 59-CAACGG [2]), would suggest that Sucnr1 functions more as a sensor GTTCTTCTGTTAGTCC-39; and primer 3, 59-AAGAACAA of metabolic (or oxidative) damage (19) rather than ATGGTAGAACAGTCACGG-39. A PCR product of ;500 a physiological mediator of signaling. nucleotides (nt) was obtained from WT DNA, whereas Mounting evidence points to an important role for mutant DNA produced an amplification product of Sucnr1 during periods of metabolic dysfunction, such as ;320 nt in size. These KO-first mice were designated GT diabetes-related hypertension, oxygen-induced retinopa- mice. In order to remove the critical exon of the Sucnr1 gene, thy, and the metabolic syndrome (19). Interestingly, together with the neomycin cassette, GT mice were crossed obesity is a key component of many metabolic-related with Sox2-Cre mice (supplied by Dr. Miguel Torres, Centro diseases (20) and can lead to diabetes, hyperlipidemia, Nacional de Investigaciones Cardiovasculares [CNIC]) to pro- and cardiovascular disease (20,21). The effect of Sucnr1 duce whole-body KO mice. Genotyping was performed deficiency on body composition and metabolism has not as before using the primer 4, 59-ACTTCCAGTTCAACAT previously been studied. We reasoned that Sucnr1 could CAGCCGCTACA-39;primer5,59-GTGATTCATCTGTATTAT be a potential modulator of metabolism since a recent TAGATGAGC-39; and primer 6, 59-CAGCACAACCATCAGA study indicated that this receptor participates in the GAAACAATGGACTC-39. A PCR product of ;650 nt indi- breakdown (lipolysis) of stored triglycerol (TG) in fat cated that recombination had occurred to produce a KO (22). To test this hypothesis, we analyzed the expression locus, and a product of ;300 nt identified a WT locus. All of Sucnr1 in mouse adipose tissue and observed high experiments were carried out using these KO mice. expression in the white adipocyte compartment. To gain Mice were housed at the CNIC animal facility under insight into the (patho)physiological role of Sucnr1, we pathogen-free conditions. Male mice were used for all created mice deficient for this gene using a knockout studies. Mice were given ad libitum access to food and (KO)-first approach. We show that deficiency of the water unless otherwise noted in experimental methods. Sucnr1 gene has metabolic consequences for weight gain Environmental conditions were controlled to 12/12-h and glucose homeostasis. Sucnr1 KO mice have a modest light/dark cycles. Animal studies were approved by the lean phenotype under standard diet (SD) conditions, cor- local ethics committee. All animal procedures conformed relating with a reduction in the size of white adipose to European Union Directive 86/609/EEC and recommen- tissue (WAT) depots, increased energy expenditure, and dation 2007/526/EC regarding the protection of animals an improved glucose clearance rate. Challenge with high- used for experimental and other scientific purposes, fat diet (HFD) also resulted in a significant decrease in enacted under Spanish law 1201/2005. Male Sucnr1 KO body weight in Sucnr1 KO mice, but only during initial mice and WT mice (5–6 weeks old) obtained from hetero- periods. At later periods, body weight of Sucnr1 KO mice zygous mating were fed an SD of rodent chow, containing was indistinguishable from wild-type (WT) littermates, 13.4% fat (16% energy; Diet 5K67, LabDiet, Saint Louis, but WAT content was increased. This appeared to coincide MO) or an HFD containing 34.9% fat (60.9% energy; with a hyperglycemic profile and a reduction in insulin Diet58Y1,TestDiet,SaintLouis,MO).Bodyweight secretion from the pancreas. Collectively, our results was recorded weekly. Separate cohorts of animals on point to a potentially important role for Sucnr1 in meta- SD and HFD were used for metabolic cage analysis using bolic disease related with obesity. a 16-chamber indirect calorimetry system (PhenoMaster; TSE Systems, Bad Homburg, Germany). Mice were indi- RESEARCH DESIGN AND METHODS vidually housed in the chambers for 5 days; the first Generation of Sucnr1-Mutant Mice, Feeding Regimes, 2 days were used for acclimatization, and data were ana- and Indirect Calorimetry lyzed from the last 3 days. Oxygen consumption rate, To create Sucnr1-mutant mice, we obtained two Sucnr1- carbon dioxide production rate, feeding, and total loco- targeted embryonic stem (ES) cell clones from the European motive activity were measured concurrently for each Mouse Mutagenesis Consortium (EUCOMM), designated as mouse. KO-first, conditional-readyEScells(23).Thisflexible system allows both for gene-trap (GT) reporter constructs and also MRI and Spectroscopy Analysis for conditional and null alleles to be generated by exposure Imaging was performed in the Advanced
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