TY - JOUR
T1 - Loss of growth hormone–mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity
AU - Chhabra, Yash
AU - Nelson, Caroline N.
AU - Plescher, Monika
AU - Barclay, Johanna L.
AU - Smith, Aaron G.
AU - Andrikopoulos, Sof
AU - Mangiafico, Salvatore
AU - Waxman, David J.
AU - Brooks, Andrew J.
AU - Waters, Michael J.
N1 - Funding Information:
The authors thank The University of Queensland Institute for Molecular Biosciences Animal House Facility for animal husbandry services. The research was supported by National Health and Medical Research Council grants 1083612 (to A.G.S.), 1124026 (to A.J.B.), and 401668 (to M.J.W.). D.J.W. was supported, in part, by U.S. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Grant DK033765. The authors declare no conflicts of interest
Publisher Copyright:
© FASEB
PY - 2019/5/1
Y1 - 2019/5/1
N2 - Growth hormone (GH) has an important function as an insulin antagonist with elevated insulin sensitivity evident in humans and mice lacking a functional GH receptor (GHR). We sought the molecular basis for this sensitivity by utilizing a panel of mice possessing specific deletions of GHR signaling pathways. Metabolic clamps and glucose homeostasis tests were undertaken in these obese adult C57BL/6 male mice, which indicated impaired hepatic gluconeogenesis. Insulin sensitivity and glucose disappearance rate were enhanced in muscle and adipose of mice lacking the ability to activate the signal transducer and activator of transcription (STAT)5 via the GHR (Ghr-391−/−) as for GHR-null (GHR−/−) mice. These changes were associated with a striking inhibition of hepatic glucose output associated with altered glycogen metabolism and elevated hepatic glycogen content during unfed state. The enhanced hepatic insulin sensitivity was associated with increased insulin receptor β and insulin receptor substrate 1 activation along with activated downstream protein kinase B signaling cascades. Although phosphoenolpyruvate carboxykinase (Pck)-1 expression was unchanged, its inhibitory acetylation was elevated because of decreased sirtuin-2 expression, thereby promoting loss of PCK1. Loss of STAT5 signaling to defined chromatin immunoprecipitation targets would further increase lipogenesis, supporting hepatosteatosis while lowering glucose output. Finally, up-regulation of IL-15 expression in muscle, with increased secretion of adiponectin and fibroblast growth factor 1 from adipose tissue, is expected to promote insulin sensitivity.—Chhabra, Y., Nelson, C. N., Plescher, M., Barclay, J. L., Smith, A. G., Andrikopoulos, S., Mangiafico, S., Waxman, D. J., Brooks, A. J., Waters, M. J. Loss of growth hormone-mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity. FASEB J. 33, 6412–6430 (2019). www.fasebj.org.
AB - Growth hormone (GH) has an important function as an insulin antagonist with elevated insulin sensitivity evident in humans and mice lacking a functional GH receptor (GHR). We sought the molecular basis for this sensitivity by utilizing a panel of mice possessing specific deletions of GHR signaling pathways. Metabolic clamps and glucose homeostasis tests were undertaken in these obese adult C57BL/6 male mice, which indicated impaired hepatic gluconeogenesis. Insulin sensitivity and glucose disappearance rate were enhanced in muscle and adipose of mice lacking the ability to activate the signal transducer and activator of transcription (STAT)5 via the GHR (Ghr-391−/−) as for GHR-null (GHR−/−) mice. These changes were associated with a striking inhibition of hepatic glucose output associated with altered glycogen metabolism and elevated hepatic glycogen content during unfed state. The enhanced hepatic insulin sensitivity was associated with increased insulin receptor β and insulin receptor substrate 1 activation along with activated downstream protein kinase B signaling cascades. Although phosphoenolpyruvate carboxykinase (Pck)-1 expression was unchanged, its inhibitory acetylation was elevated because of decreased sirtuin-2 expression, thereby promoting loss of PCK1. Loss of STAT5 signaling to defined chromatin immunoprecipitation targets would further increase lipogenesis, supporting hepatosteatosis while lowering glucose output. Finally, up-regulation of IL-15 expression in muscle, with increased secretion of adiponectin and fibroblast growth factor 1 from adipose tissue, is expected to promote insulin sensitivity.—Chhabra, Y., Nelson, C. N., Plescher, M., Barclay, J. L., Smith, A. G., Andrikopoulos, S., Mangiafico, S., Waxman, D. J., Brooks, A. J., Waters, M. J. Loss of growth hormone-mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity. FASEB J. 33, 6412–6430 (2019). www.fasebj.org.
KW - gluconeogenesis
KW - hepatic glucose output
KW - metabolism
UR - http://www.scopus.com/inward/record.url?scp=85065509291&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065509291&partnerID=8YFLogxK
U2 - 10.1096/fj.201802328R
DO - 10.1096/fj.201802328R
M3 - Article
C2 - 30779881
AN - SCOPUS:85065509291
SN - 0892-6638
VL - 33
SP - 6412
EP - 6430
JO - FASEB Journal
JF - FASEB Journal
IS - 5
ER -