Protein kinase A induces UCP1 expression in specific adipose depots to increase energy expenditure and improve metabolic health.
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.
Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, Illinois;
Lorna M
LM
Dickson
Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, Illinois;
Shriya
S
Gandhi
Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois.
Brian T
BT
Layden
Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, Illinois;
Ronald N
RN
Cohen
Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, Illinois; Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and barton.wicksteed@northwestern.edu.
Barton
B
Wicksteed
D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D050154:Adiposity; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000494:pharmacology*; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000502:physiology*; D018149:Glucose Intolerance; D006304:Health Status; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000071256:Uncoupling Protein 1 / Q000096:biosynthesis* / Q000187:drug effects; D015430:Weight Gain
D052242:Adiponectin; C499919:Adipoq protein, mouse; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D017868:Cyclic AMP-Dependent Protein Kinases
adipose; energy expenditure; protein kinase A; uncoupling protein 1