Interacting Effects of TSH and Insulin on Human Differentiated Adipocytes

D. Felske; A. Gagnon; A. Sorisky

doi:10.1055/s-0034-1395673

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2015; 47(09): 681-685
DOI: 10.1055/s-0034-1395673

Endocrine Research

Interacting Effects of TSH and Insulin on Human Differentiated Adipocytes

D. Felske

¹Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

²Departments of Medicine and of Biochemistry, Microbiology & Immunology, University of Ottawa, Ontario, Canada

,

A. Gagnon

¹Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

²Departments of Medicine and of Biochemistry, Microbiology & Immunology, University of Ottawa, Ontario, Canada

,

A. Sorisky

¹Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

²Departments of Medicine and of Biochemistry, Microbiology & Immunology, University of Ottawa, Ontario, Canada

› Author Affiliations

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.

Key words

Akt - protein kinase C - lipolysis

Full Text

References

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