3,5‐Diiodo‐L‐thyronine prevents high‐fat‐diet‐induced insulin resistance in rat skeletal muscle through metabolic and structural adaptations

Abstract

The worldwide prevalence of obesity-associated pathologies, including type 2 diabetes, requires thorough investigation of mechanisms and interventions. Recent studies have highlighted thyroid hormone analogs and derivatives as potential agents able to counteract such pathologies. In this study, in rats receiving a high-fat diet (HFD), we analyzed the effects of a 4-wk daily administration of a naturally occurring iodothyronine, 3,5-diiodo-L-thyronine (T2), on the gastrocnemius muscle metabolic/structural phenotype and insulin signaling. The HFD-induced increases in muscle levels of fatty acid translocase (3-fold; P<0.05) and TGs (2-fold, P<0.05) were prevented by T2 (each; P<0.05 vs. HFD). T2 increased insulin-stimulated Akt phosphorylation levels (∼2.5-fold; P<0.05 vs. HFD). T2 induced these effects while sparing muscle mass and without cardiac hypertrophy. T2 increased the muscle contents of fast/glycolytic fibers (2-fold; P<0.05 vs. HFD) and sarcolemmal glucose transporter 4 (3-fold; P<0.05 vs. HFD). Adipocyte differentiation-related protein was predominantly present within the slow/oxidative fibers in HFD-T2. In T2-treated rats (vs. HFD), glycolytic enzymes and associated components were up-regulated (proteomic analysis, significance limit: 2-fold; P<0.05), as was phosphofructokinase activity (by 1.3-fold; P<0.05), supporting the metabolic shift toward a more glycolytic phenotype. These results highlight T2 as a potential therapeutic approach to the treatment of diet-induced metabolic dysfunctions.

Translating Pharmacological Findings from Hypothyroid Rodents to Euthyroid Humans: Is There a Functional Role of Endogenous 3,5-T2?

“…In particular, this link is in accordance with animal studies showing that 3,5-T2 was only a third as potent as T3 in suppressing TSH concentrations, and rather high pharmacological 3,5-T2 concentrations are required for TSH suppression (34)(35)(36). However, several animal studies in rodents and other species, for example killifish, indicated that 3,5-T2 interferes with the hypothalamus-pituitary-thyroid axis at several levels such as pituitary, thyroid, and peripheral action, thereby displaying a broad spectrum of mechanisms involved such as classical interaction with TR and also rapid effects at the cell membrane and mitochondria (10,12,14,(34)(35)(36)(37)(38)(39)(40) (for a review, see (3)). Action of 3,5-T2 via these different targets and molecular mechanisms might occur at different 3,5-T2 concentrations and depend on acute or chronic exposure (35,37,40), thus possibly explaining the unexpected bell-shaped relationship with serum TSH.…”

“…According to the promising effects of pharmacological interventions with 3,5-T2 on body weight or blood lipid profile (10,12,14,49), missing associations toward related measures require a clarifying note. To ensure an effect on resting metabolic rate, most of the studies used a daily intraperitoneal injection of 25 lg 3,5-T2 per 100 g body weight (10,12,14), and rather high doses were needed for oral administration in humans and rodents (49,50).…”

“…To ensure an effect on resting metabolic rate, most of the studies used a daily intraperitoneal injection of 25 lg 3,5-T2 per 100 g body weight (10,12,14), and rather high doses were needed for oral administration in humans and rodents (49,50). In detail, a chronic treatment with 3,5-T2 at doses of up to 900 lg per day led to a significant weight loss in one human study (49), a 3,5-T2 dose ninefold higher than average daily thyroidal production of T4, the putative precursor of 3,5-T2, which is only a minor metabolite of T4 according to previous kinetic studies (17,18).…”

“…Furthermore, administered in pharmacological doses, 3,5-T2 prevented rodents from weight gain from a high-fat diet (12) and restrained the development of insulin resistance (10). Possible discussed underlying mechanisms included the activation of thermogenesis (13), the prevention of fat accumulation in skeletal muscle as well as in the liver (10,14), and the enhancement of lipolysis (10,12,13), together resulting in remarkable antisteatotic effects under high-fat diet conditions.…”

Thyroid: biological actions of ‘nonclassical’ thyroid hormones

“…T 2 , as a nonclassical TH, is able to prevent BW gain when administered i.p. to rats fed a high-fat diet without inducing T 3 -related undesirable side effects (tachycardia, cardiac hyperplasia, and decreased TSH levels), at least at the administered dose (25 mg/100 g BW for 4 weeks) (Lanni et al 2005, De Lange et al 2011, Moreno et al 2011. At this dose, by almost doubling hepatic FA oxidation rate, T 2 efficiently prevented HFD-induced i) hepatic fat accumulation, ii) insulin resistance, and iii) increase in serum triglycerides (TGs) and cholesterol levels (Lanni et al 2005).…”