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      Protein kinase A induces UCP1 expression in specific adipose depots to increase energy expenditure and improve metabolic health

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          Abstract

          Adipose tissue PKA has roles in adipogenesis, lipolysis, and mitochondrial function. PKA transduces the cAMP signal downstream of G protein-coupled receptors, which are being explored for therapeutic manipulation to reduce obesity and improve metabolic health. This study aimed to determine the overall physiological consequences of PKA activation in adipose tissue. Mice expressing an activated PKA catalytic subunit in adipose tissue (Adipoq-caPKA mice) showed increased PKA activity in subcutaneous, epididymal, and mesenteric white adipose tissue (WAT) depots and brown adipose tissue (BAT) compared with controls. Adipoq-caPKA mice weaned onto a high-fat diet (HFD) or switched to the HFD at 26 wk of age were protected from diet-induced weight gain. Metabolic health was improved, with enhanced insulin sensitivity, glucose tolerance, and β-cell function. Adipose tissue health was improved, with smaller adipocyte size and reduced macrophage engulfment of adipocytes. Using metabolic cages, we found that Adipoq-caPKA mice were shown to have increased energy expenditure, but no difference to littermate controls in physical activity or food consumption. Immunoblotting of adipose tissue showed increased expression of uncoupling protein-1 (UCP1) in BAT and dramatic UCP1 induction in subcutaneous WAT, but no induction in the visceral depots. Feeding a HFD increased PKA activity in epididymal WAT of wild-type mice compared with chow, but did not change PKA activity in subcutaneous WAT or BAT. This was associated with changes in PKA regulatory subunit expression. This study shows that adipose tissue PKA activity is sufficient to increase energy expenditure and indicates that PKA is a beneficial target in metabolic health.

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          Author and article information

          Journal
          Am J Physiol Regul Integr Comp Physiol
          Am. J. Physiol. Regul. Integr. Comp. Physiol
          ajpregu
          ajpregu
          AJPREGU
          American Journal of Physiology - Regulatory, Integrative and Comparative Physiology
          American Physiological Society (Bethesda, MD )
          0363-6119
          1522-1490
          20 April 2016
          1 July 2016
          1 July 2017
          : 311
          : 1
          : R79-R88
          Affiliations
          [1] 1Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, Illinois;
          [2] 2Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and
          [3] 3Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
          Author notes
          Address for reprint requests and other correspondence: B. Wicksteed, Div. of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern Univ., 320 East Superior St., Chicago, IL 60611 (e-mail: barton.wicksteed@ 123456northwestern.edu ).
          Article
          PMC4967236 PMC4967236 4967236 R-00114-2016
          10.1152/ajpregu.00114.2016
          4967236
          27097660
          0d56bcda-7aba-453f-a130-e1444eea8811
          History
          : 28 March 2016
          : 18 April 2016
          Funding
          Funded by: 100000062 HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
          Award ID: DK085129
          Award ID: DK020595
          Award ID: DK104927
          Award ID: DK020595
          Award ID: DK104927
          Funded by: 100000041 American Diabetes Association (ADA)
          Award ID: 7-13-BS-033
          Funded by: 100000738 U.S. Department of Veterans Affairs (VA)
          Award ID: 1IK2BX001587-01
          Categories
          Obesity, Diabetes and Energy Homeostasis

          energy expenditure,protein kinase A,adipose,uncoupling protein 1

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