Subscribe to RSS
DOI: 10.1055/s-0034-1395673
Interacting Effects of TSH and Insulin on Human Differentiated Adipocytes
Publication History
received 24 September 2014
accepted 20 November 2014
Publication Date:
12 December 2014 (online)
Abstract
Subclinical hypothyroidism, characterized by an isolated rise in TSH serum levels with normal thyroid function, is a pro-inflammatory state associated with insulin resistance. Adipocytes express TSH receptors, but it is not known if TSH can directly inhibit insulin signaling. Using primary human differentiated adipocytes, we examined the effects of TSH on insulin-stimulated Akt phosphorylation, and whether conventional PKC (cPKC) were involved. The effect of insulin on TSH-stimulated lipolysis was also investigated. TSH inhibited insulin-stimulated Akt phosphorylation in adipocytes by 54%. TSH activated cPKC, and Gö6976, a PKCα and -β1 inhibitor, prevented the inhibitory effect of TSH on the insulin response. Insulin reduced the ability of TSH to activate cPKC and to stimulate lipolysis.
Our data reveal novel interactions between TSH and insulin. TSH inhibits insulin-stimulated Akt signaling in a cPKC-dependent fashion, whereas insulin blocks TSH-stimulated cPKC activity and lipolysis. TSH and insulin act on differentiated human adipocytes to modulate their respective intracellular signals.
-
References
- 1 Sorisky A, Bell A, Gagnon A. TSH receptor in adipose cells. Horm Metab Res 2000; 32: 468-474
- 2 Davies TF, Marians R, Latif R. The TSH receptor reveals itself. J Clin Invest 2002; 110: 161-164
- 3 Marcus C, Ehrén H, Bolme P, Arner P. Regulation of lipolysis during the neonatal period. Importance of thyrotropin. J Clin Invest 1988; 82: 1793-1797
- 4 Antunes TT, Gagnon A, Langille ML, Sorisky A. Thyroid-stimulating hormone induces interleukin-6 release from human adipocytes through activation of the nuclear factor-κB pathway. Endocrinology 2008; 149: 3062-3066
- 5 Gagnon A, Antunes TT, Ly T, Pongsuwan P, Gavin C, Lochnan HA, Sorisky A. TSH-stimulates lipolysis in adipocytes in culture and raises serum free fatty acid levels in vivo. Metabolism 2010; 59: 547-553
- 6 Gagnon A, Langille ML, Chaker S, Antunes TT, Durand J, Sorisky A. TSH signaling pathways that regulate MCP-1 in human differentiated adipocytes. Metabolism 2014; 63: 812-821
- 7 Antunes TT, Gagnon A, Chen B, Pacini F, Smith TJ, Sorisky A. Interleukin-6 release from human abdominal adipose cells is regulated by thyroid-stimulating hormone: effect of adipocyte differentiation and anatomic depot. Am J Physiol Endocrinol Metab 2006; 290: E1140-E1144
- 8 Dardano A, Ghiadoni L, Plantinga Y, Caraccio N, Bemi A, Duranti E, Taddei S, Ferrannini E, Salvetti A, Monzani F. Recombinant human TSH reduces endothelium-dependent vasodilation in patients monitored for differentiated thyroid carcinoma. J Clin Endocrinol Metab 2006; 91: 4175-4178
- 9 Santini F, Galli G, Maffei M, Fierabracci P, Pelosini C, Marsili A, Giannetti M, Castagna MG, Checchi S, Molinaro E, Piaggi P, Pacini F, Elisei R, Vitti P, Pinchera A. Acute exogenous TSH administration stimulates leptin secretion in vivo. Eur J Endocrinol 2010; 163: 63-67
- 10 Taddei S, Caraccio N, Virdis A, Dardano A, Versari DLG, Salvetti A, Ferrannini E, Monzani F. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab 2003; 88: 3731-3737
- 11 Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L, Ferrannini E, Salvetti A, Monzani F. Low-grade systemic inflammation causes endothelial dysfunction in patients with Hashimoto’s thyroiditis. J Clin Endocrinol Metab 2006; 91: 5076-5082
- 12 Caraccio N, Natali A, Sironi A, Baldi S, Frascerra S, Dardano A, Monzani F, Ferrannini E. Muscle metabolism and exercise tolerance in subclinical hypothyroidism: a controlled trial of levothyroxine. J Clin Endocrinol Metab 2005; 90: 4057-4062
- 13 Rodondi N, Bauer DC. Subclinical hypothyroidism and cardiovascular risk: how to end the controversy. J Clin Endocrinol Metab 2013; 98: 2267-2269
- 14 Solini A, Monzani F. Hypothyroidism and intermediate metabolism: a complex relationship. Thyroid 2010; 20: 837-839
- 15 Dessein PH, Joffe BI, Stanwix AE. Subclinical hypothyroidism is associated with insulin resistance in rheumatoid arthritis. Thyroid 2004; 14: 443-446
- 16 Maratou E, Hadjidakis DJ, Kollias A, Tsegka K, Peppa M, Alevizaki M, Mitrou P, Lambadiari V, Boutati E, Nikzas D, Tountas N, Economopoulos T, Raptis SA, Dimitriadis G. Studies of insulin resistance in patients with clinical and subclinical hypothyroidism. Eur J Endocrinol 2009; 160: 785-790
- 17 Liu C, Scherbaum WA, Schott M, Schinner S. Subclinical hypothyroidism and the prevalence of the metabolic syndrome. Horm Metab Res 2011; 43: 417-421
- 18 Gagnon A, Foster C, Landry A, Sorisky A. The role of interleukin 1b in the anti-adipogenic action of macrophages on human preadipocytes. J Endocrinol 2013; 217: 197-206
- 19 Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227: 680-685
- 20 Thrush AB, Gagnon A, Sorisky A. PKC activation is required for TSH-mediated lipolysis via perilipin activation. Horm Metab Res 2012; 44: 825-831
- 21 Copps KD, White MF. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 2012; 55: 2565-2582
- 22 Kimura I, Ozawa K, Inoue D, Imamura T, Kimura K, Maeda T, Terasawa K, Kashihara D, Hirano K, Tani T, Takahashi T, Miyauchi S, Shioi G, Inoue H, Tsujimoto G. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nature Commun 2013; 4: 1829
- 23 Li L, Sampat K, Hu N, Zakari J, Yuspa SH. Protein kinase C negatively regulates Akt activity and modifies UVC-induced apoptosis in mouse keratinocytes. J Biol Chem 2006; 281: 3237-3243
- 24 Rozengurt E, Sinnett-Smith J, Kisfalvi K. Crosstalk between insulin/insulin-like growth factor-1 receptors and G protein-coupled receptor signaling systems: a novel target for the antidiabetic drug metformin in pancreatic cancer. Clin Cancer Res 2010; 16: 2505-2511
- 25 Garcia B, Santisteban P. PI3K is involved in the IGF-I inhibition of TSH-induced sodium/iodide symporter gene expression. Mol Endocrinol 2002; 16: 342-352