Expression of functional TSH receptor in white adipose tissues of hyt/hyt mice induces lipolysis in vivo

Abstract

To determine the relative importance of TSH in white adipose tissue, we compared the adipose phenotypes of two distinct mouse models of hypothyroidism. These models differed in that the normal reciprocal relationship between thyroid hormone and TSH was intact in one and disrupted in the other. One model, thyroidectomized (THYx) mice, had a 100-fold increase in TSH and a normal TSH receptor (TSHR); in contrast, the other model, hyt/hyt mice, had a 120-fold elevation of TSH but a nonfunctional TSHR. Although both THYx and hyt/hyt mice were in a severe hypothyroid state, the epididymal fat (mg)/body wt (g) (F/B) ratio of THYx mice was much smaller than that of hyt/hyt mice (8.2 ± 0.43 vs. 14.4 ± 0.40, respectively, P < 0.001). The fat cell diameter in THYx mice was also smaller than that in hyt/hyt mice (79 ± 2.8 vs. 105 ± 2.2 μm, respectively, P < 0.001), suggesting that TSH induced lipolysis in adipose tissues. When we transferred a functional mouse TSHR gene and a control plasmid into opposite sides of epididymal fat of hyt/hyt mice by plasmid injection combined with electroporation, fat weight of the TSHR side was decreased to 60% of that of the control side. Messenger RNA levels of hormone-sensitive lipase in epididymal fat containing the transferred TSHR gene were twofold higher than those in tissue from the control side. These results indicated that TSH worked as a lipolytic factor in white adipose tissues, especially in mice in a hypothyroid state.

Thyroid-stimulating hormone stimulation downregulates autophagy and promotes apoptosis in chondrocytes

“…In the present study, our first finding is that TSH has a negative effect on the proliferation of PMCs, and thus gave a direct evidence for the relationship between the pituitary axis and the skeletal system. This is consistent with the study of Endo et al that high serum TSH contributes to the growth retardation in the affected animals by comparing two distinct mouse models of hypothyroidism with or without a functional TSHR [19]. Our study provides the direct cellular basis underlying the phenotype they observed.…”

“…However, the role of TSH on non-thyroid tissues is under debate. It was reported that TSH stimulated the proliferation of vascular smooth muscle cells [17] and have a direct role in the progression of atherosclerosis by regulating blood sugar and lipid metabolism [17][18][19]. However, TSH is a negative regulator in bone remodeling by inhibiting osteoclast mediated bone resorption [20,21].…”

Dissecting adipose tissue lipolysis: molecular regulation and implications for metabolic disease

“…Thyroid-stimulating hormone (TSH) and the melanocortins (MCs) adrenocorticotrophic hormone (ACTH) and melanocyte-stimulating hormone stimulate AC by activation of the G s -coupled TSH receptor (Laugwitz et al 1996, Endo & Kobayashi 2012) and MC receptors (Cho et al 2005, Rodrigues et al 2013) respectively (Fig. 3).…”

Thyroid Function and Obesity

“…In the complex system of hypothalamic regulation, the factor favoured by most authors when discussing the cause for activation of the thyroid in overweight is activation of hypothalamic centres by leptin released from adipocytes in fat tissue [19,29,30,31]. There is a complex interaction between the thyroid hormones and adipose tissue where TSH and thyroid hormones may participate in adipocyte differentiation [32] and lipolysis regulation [33], whereas various adipocyte cytokines may interact with the hypothalamic-pituitary-thyroid axis [34,35,36]. …”