TY - JOUR
T1 - Regulation of lipolytic response and energy balance by melanocortin 2 receptor accessory protein (MRAP) in adipocytes
AU - Zhang, Xiaodong
AU - Saarinen, Alicia M.
AU - Campbell, Latoya E.
AU - De Filippis, Elena A.
AU - Liu, Jun
N1 - Funding Information:
Acknowledgments. The authors thank Dr. James Madura, Dr. Paul Magtibay, and Judy Tiede (Mayo Clinic, Arizona) for collecting the human adipose tissue at the time of surgery. The authors also thank Dr. Xin-Yun Huang (Cornell University) for helpful discussions and Carly C. Wilcox (Mayo Clinic, Arizona) for her technical assistance. Funding. This work was supported by research grants from the Arizona Biomedical Research Commission (Early Investigator Grant ADHS14-00003606 to E.A.D.F.) and the National Institute of Diabetes and Digestive and Kidney Diseases (DK089178 and DK109096 to J.L.). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. X.Z. designed and performed the research, analyzed data, and wrote the manuscript. A.M.S. and L.E.C. performed research and analyzed the data. E.A.D.F. performed research and revised the manuscript. J.L. designed and supervised the study and wrote the manuscript. J.L. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented at the 77th Scientific Sessions of the American Diabetes Association, San Diego, CA, 9–13 June 2015.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - Melanocortin 2 receptor accessory protein (MRAP) is highly expressed in adrenal gland and adipose tissue. In adrenal cells, MRAP is essential for adrenocorticotropic hormone (ACTH)–induced activation of the cAMP/protein kinase A (PKA) pathway by melanocortin 2 receptor (MC2R), leading to glucocorticoid production and secretion. Although ACTH was known to stimulate PKA-dependent lipolysis, the functional involvement of MRAP in adipocyte metabolism remains incompletely defined. Herein, we found that knockdown or overexpression of MRAP in 3T3-L1 adipocytes reduced or increased ACTH-induced lipolysis, respectively. Moreover, an unbiased proteomics screen and coimmunoprecipitation analysis identified Gas as a novel interacting partner of MRAP. An MRAP mutant disabled in Gas association failed to augment the activation of PKA and lipolytic response to ACTH. Furthermore, compared with wild-type mice, transgenic mice (aP2-MRAP) overexpressing MRAP fat specifically exhibited increased lipolytic response to ACTH. When fed a high-fat diet (HFD), the transgenic mice displayed a significant decrease in the gain of adiposity and body weight as well as an improvement in glucose and insulin tolerance. These phenotypes were accompanied by increased adipose expression of genes for mitochondrial fatty acid oxidation and thermogenesis, and overall energy expenditure. Collectively, our data strongly suggest that MRAP plays a critical role in the regulation of ACTH-induced adipose lipolysis and whole-body energy balance.
AB - Melanocortin 2 receptor accessory protein (MRAP) is highly expressed in adrenal gland and adipose tissue. In adrenal cells, MRAP is essential for adrenocorticotropic hormone (ACTH)–induced activation of the cAMP/protein kinase A (PKA) pathway by melanocortin 2 receptor (MC2R), leading to glucocorticoid production and secretion. Although ACTH was known to stimulate PKA-dependent lipolysis, the functional involvement of MRAP in adipocyte metabolism remains incompletely defined. Herein, we found that knockdown or overexpression of MRAP in 3T3-L1 adipocytes reduced or increased ACTH-induced lipolysis, respectively. Moreover, an unbiased proteomics screen and coimmunoprecipitation analysis identified Gas as a novel interacting partner of MRAP. An MRAP mutant disabled in Gas association failed to augment the activation of PKA and lipolytic response to ACTH. Furthermore, compared with wild-type mice, transgenic mice (aP2-MRAP) overexpressing MRAP fat specifically exhibited increased lipolytic response to ACTH. When fed a high-fat diet (HFD), the transgenic mice displayed a significant decrease in the gain of adiposity and body weight as well as an improvement in glucose and insulin tolerance. These phenotypes were accompanied by increased adipose expression of genes for mitochondrial fatty acid oxidation and thermogenesis, and overall energy expenditure. Collectively, our data strongly suggest that MRAP plays a critical role in the regulation of ACTH-induced adipose lipolysis and whole-body energy balance.
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U2 - 10.2337/db17-0862
DO - 10.2337/db17-0862
M3 - Article
C2 - 29217655
AN - SCOPUS:85041199016
VL - 67
SP - 222
EP - 234
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 2
ER -