title: Thyroid-stimulating hormone improves insulin sensitivity in skeletal muscle cells via cAMP/PKA/CREB pathway-dependent upregulation of insulin receptor substrate-1 expression.
abstract: Thyroid-stimulating hormone (TSH) receptor is expressed in extrathyroidal tissues such as hepatocytes, adipocytes, and skeletal muscle, which suggests a possible novel role of TSH in various metabolic processes in extrathyroidal tissues independent of thyroid hormones. We investigated whether TSH has any effects on glucose tolerance and insulin sensitivity in the skeletal muscle using diet-induced obesity (DIO) mouse models and rodent skeletal muscle cells. TSH improved glucose tolerance in DIO mice and this was associated with an improvement of skeletal muscle insulin sensitivity resulting from the increased expression of insulin receptor substrate (IRS)-1 protein and mRNA therein. TSH significantly increased both basal and insulin-stimulated glucose transport in rat L6 myotubes and increased the expression of IRS-1 protein and mRNA in these cells as well. TSH also stimulated Irs1 promoter activation; this stimulation was abolished by protein kinase A (PKA) inhibition using H89 or by mutation of the cAMP-response element site located at -1155 to -875 bp of the Irs1 promoter region, supporting a novel role of TSH activated-cAMP/PKA/CREB signaling in the regulation of Irs1 expression. In conclusion, TSH improves insulin sensitivity in skeletal muscle by increasing Irs1 gene expression. This regulatory effect is mediated by a PKA-CREB-dependent pathway.
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea; Department of Internal Medicine, Boramae Medical Center, Seoul, 07061, Republic of Korea.
authors.forename: Min Kyong
authors.initials: MK
authors.lastname: Moon
authors.affiliation: Seoul National University Hospital Biomedical Research Institute, Seoul, 03080, Republic of Korea.
authors.forename: Geun Hyung
authors.initials: GH
authors.lastname: Kang
authors.affiliation: Seoul National University Hospital Biomedical Research Institute, Seoul, 03080, Republic of Korea.
authors.forename: Hwan Hee
authors.initials: HH
authors.lastname: Kim
authors.affiliation: Seoul National University Hospital Biomedical Research Institute, Seoul, 03080, Republic of Korea.
authors.forename: Sun Kyoung
authors.initials: SK
authors.lastname: Han
authors.affiliation: Seoul National University Hospital Biomedical Research Institute, Seoul, 03080, Republic of Korea.
authors.forename: Young Do
authors.initials: YD
authors.lastname: Koo
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea; Seoul National University Hospital Biomedical Research Institute, Seoul, 03080, Republic of Korea.
authors.forename: Sun Wook
authors.initials: SW
authors.lastname: Cho
authors.affiliation: Seoul National University Hospital Biomedical Research Institute, Seoul, 03080, Republic of Korea; Seoul National University Hospital Healthcare System Gangnam Center, Seoul, 06236, Republic of Korea.
authors.forename: Ye An
authors.initials: YA
authors.lastname: Kim
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University Graduate School of Medicine, Incheon, 21999, Republic of Korea.
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Oh
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea; Seoul National University Hospital Biomedical Research Institute, Seoul, 03080, Republic of Korea.
authors.forename: Do Joon
authors.initials: do J
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea; Seoul National University Hospital Biomedical Research Institute, Seoul, 03080, Republic of Korea.
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Chung
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea; Seoul National University Hospital Biomedical Research Institute, Seoul, 03080, Republic of Korea.
authors.forename: Kyong Soo
authors.initials: KS
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea; Seoul National University Hospital Biomedical Research Institute, Seoul, 03080, Republic of Korea. Electronic address: yjparkmd@snu.ac.kr.
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Park
mesh_terms: D000818:Animals; D001483:Base Sequence; D001692:Biological Transport / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D059305:Diet, High-Fat; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics* / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013972:Thyrotropin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D013972:Thyrotropin; D002784:Cholesterol; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose
keywords: Insulin receptor substrate-1; Insulin sensitivity; Skeletal muscle; Thyroid-stimulating hormone