Pharmacological Activation of Thyroid Hormone Receptors Elicits a Functional Conversion of White to Brown Fat

Abstract

Summary The functional conversion of white adipose tissue (WAT) into a tissue with brown adipose tissue (BAT)-like activity, often referred to a ‘browning’, represents an intriguing strategy to combat obesity and metabolic disease. We demonstrate that thyroid hormone receptor (TR) activation by a synthetic agonist markedly induces a program of adaptive thermogenesis in subcutaneous WAT that coincides with a restoration of cold tolerance to cold-intolerant mice. Distinct from most other browning agents, pharmacological TR activation dissociates the browning of WAT from activation of classical BAT. TR agonism also induces the browning of white adipocytes in vitro, indicating that TR mediated browning is cell autonomous. These data establish TR agonists as a class of browning agents, implicate the TRs in the browning of WAT, and suggest a profound pharmacological potential of this action.

Changes in Thyroid Hormone Levels Within the Normal and/or Subclinical Hyper- or Hypothyroid Range Do Not Affect Circulating Irisin Levels in Humans

“…Thyroid hormones are known to increase energy expenditure (2) and have been used towards this end in the past (3). Recently, it was shown that activation of thyroid hormone receptors induces browning of white fat, accompanied with a marked increase in Uncoupling Protein 1 (UCP1) gene expression (4).…”

Mechanisms of metabolic dysfunction in cancer-associated cachexia

“…Recently, browning of WAT has been shown to take part in the pathogenesis of hypermetabolism commonly observed in other morbid conditions, like post-burn injury, severe adrenergic stress, and kidney failure (Kir et al 2015;Patsouris et al 2015;Sidossis et al 2015). Treatment of mice with a synthetic thyroid hormone receptor agonist induces adaptive thermogenesis in subcutaneous WAT, thus suggesting a role for WAT browning also in hyperthyroidism (Lin et al 2015).…”

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…Primarily by hepatic action, thyroid hormone therapy can lower the circulating concentration of cholesterol and lipoproteins (Angelin and Rudling, 2010). In adipose depots, thyroid hormone can promote energy expenditure and lipolysis (Lin et al, 2015;Weiner et al, 2016). Central actions of thyroid hormone include hyperphagia and sympathetic outflow, which can also increase energy expenditure and cardiovascular adrenergic input (Lopez et al, 2010;Mittag et al, 2013).…”