title: Role of Exchange Protein Directly Activated by Cyclic AMP Isoform 1 in Energy Homeostasis: Regulation of Leptin Expression and Secretion in White Adipose Tissue.
abstract: Epacs (exchange proteins directly activated by cyclic AMP [cAMP]) act as downstream effectors of cAMP and play important roles in energy balance and glucose homeostasis. While global deletion of Epac1 in mice leads to heightened leptin sensitivity in the hypothalamus and partial protection against high-fat diet (HFD)-induced obesity, the physiological functions of Epac1 in white adipose tissue (WAT) has not been explored. Here, we report that adipose tissue-specific Epac1 knockout (AEKO) mice are more prone to HFD-induced obesity, with increased food intake, reduced energy expenditure, and impaired glucose tolerance. Despite the fact that AEKO mice on HFD display increased body weight, these mice have decreased circulating leptin levels compared to their wild-type littermates. In vivo and in vitro analyses further reveal that suppression of Epac1 in WAT decreases leptin mRNA expression and secretion by inhibiting cAMP response element binding (CREB) protein and AKT phosphorylation, respectively. Taken together, our results demonstrate that Epac1 plays an important role in regulating energy balance and glucose homeostasis by promoting leptin expression and secretion in WAT.
authors.affiliation: Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas, USA Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Yaohua
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas, USA Texas Therapeutics Institute, The University of Texas Health Science Center, Houston, Texas, USA Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Robichaux
authors.affiliation: Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas, USA Texas Therapeutics Institute, The University of Texas Health Science Center, Houston, Texas, USA Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas, USA.
authors.forename: Fang C
authors.initials: FC
authors.lastname: Mei
authors.affiliation: Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas, USA.
authors.forename: Eun Ran
authors.initials: ER
authors.lastname: Kim
authors.affiliation: Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas, USA Texas Therapeutics Institute, The University of Texas Health Science Center, Houston, Texas, USA Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas, USA.
authors.forename: Qingchun
authors.initials: Q
authors.lastname: Tong
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center, Houston, Texas, USA.
authors.forename: Jianping
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Mingxuan
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas, USA Texas Therapeutics Institute, The University of Texas Health Science Center, Houston, Texas, USA Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas, USA Graduate Program in Cell and Regulatory Biology, The University of Texas Health Science Center, Houston, Texas, USA xiaodong.cheng@uth.tmc.edu.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cheng
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D004435:Eating; D004734:Energy Metabolism; D055786:Gene Knockout Techniques; D018149:Glucose Intolerance / Q000209:etiology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D020738:Leptin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D009765:Obesity / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism
chemical_list: C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D020738:Leptin