title: Epac2a-null mice exhibit obesity-prone nature more susceptible to leptin resistance.
abstract: The exchange protein directly activated by cAMP (Epac), which is primarily involved in cAMP signaling, has been known to be essential for controlling body energy metabolism. Epac has two isoforms: Epac1 and Epac2. The function of Epac1 on obesity was unveiled using Epac1 knockout (KO) mice. However, the role of Epac2 in obesity remains unclear.
  
  
  
  To evaluate the role of Epac2 in obesity, we used Epac2a KO mice, which is dominantly expressed in neurons and endocrine tissues. Physiological factors related to obesity were analyzed: body weight, fat mass, food intake, plasma leptin and adiponectin levels, energy expenditure, glucose tolerance, and insulin and leptin resistance. To determine the mechanism of Epac2a, mice received exogenous leptin and then hypothalamic leptin signaling was analyzed.
  
  
  
  Epac2a KO mice appeared to have normal glucose tolerance and insulin sensitivity until 12 weeks of age, but an early onset increase of plasma leptin levels and decrease of plasma adiponectin levels compared with wild-type mice. Acute leptin injection revealed impaired hypothalamic leptin signaling in KO mice. Consistently, KO mice fed a high-fat diet (HFD) were significantly obese, presenting greater food intake and lower energy expenditure. HFD-fed KO mice were also characterized by greater impairment of hypothalamic leptin signaling and by weaker leptin-induced decrease in food consumption compared with HFD-fed wild-type mice. In wild-type mice, acute exogenous leptin injection or chronic HFD feeding tended to induce hypothalamic Epac2a expression.
  
  
  
  Considering that HFD is an inducer of hypothalamic leptin resistance and that Epac2a functions in pancreatic beta cells during demands of greater work load, hypothalamic Epac2a may have a role in facilitating leptin signaling, at least in response to higher metabolic demands. Thus, our data indicate that Epac2a is critical for preventing obesity and thus Epac2a activators may be used to manage obesity and obesity-mediated metabolic disorders.
authors.affiliation: Department of Physiology and Obesity-mediated Disease Research Center, Keimyung University School of Medicine, Daegu, Korea.
authors.forename: M
authors.initials: M
authors.lastname: Hwang
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Y
authors.initials: Y
authors.lastname: Go
authors.affiliation: Department of Physiology and Obesity-mediated Disease Research Center, Keimyung University School of Medicine, Daegu, Korea.
authors.forename: J-H
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Physiology and Obesity-mediated Disease Research Center, Keimyung University School of Medicine, Daegu, Korea.
authors.forename: S-K
authors.initials: SK
authors.lastname: Shin
authors.affiliation: Department of Physiology and Obesity-mediated Disease Research Center, Keimyung University School of Medicine, Daegu, Korea.
authors.forename: S E
authors.initials: SE
authors.lastname: Song
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.
authors.forename: B-C
authors.initials: BC
authors.lastname: Oh
authors.affiliation: Department of Physiology and Obesity-mediated Disease Research Center, Keimyung University School of Medicine, Daegu, Korea.
authors.forename: S-S
authors.initials: SS
authors.lastname: Im
authors.affiliation: Department of Physiology and Obesity-mediated Disease Research Center, Keimyung University School of Medicine, Daegu, Korea.
authors.forename: I
authors.initials: I
authors.lastname: Hwang
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Y H
authors.initials: YH
authors.lastname: Jeon
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: I-K
authors.initials: IK
authors.lastname: Lee
authors.affiliation: Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Seino
authors.affiliation: Department of Physiology and Obesity-mediated Disease Research Center, Keimyung University School of Medicine, Daegu, Korea.
authors.forename: D-K
authors.initials: DK
authors.lastname: Song
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000502:physiology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D002149:Energy Intake; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000473:pathology*; D054411:Receptors, Leptin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D020738:Leptin; C486707:Rapgef4 protein, mouse; D054411:Receptors, Leptin; D000242:Cyclic AMP