Thyroid hormone activates adipose tissue thermogenesis independent of uncoupling protein 1 (UCP1)

Abstract

Obesity has become a global epidemic in recent decades. It is closely linked with a number of metabolic diseases, including type 2 diabetes, cardiovascular diseases and even some types of cancers, which are threatening our health, lifespan and the quality of life. Latest studies showed that adaptive thermogenesis might be a promising strategy to combat obesity and its complications. In the classical view, brown adipose tissue (BAT) is a principle contributor for the adaptive thermogenesis via the mitochondrial protein uncoupling protein 1 (UCP1). However, UCP1-ablated mice are still able to survive cold environment, revealing the existence of alternative thermogenic pathways. On the other hand, thyroid hormones are known to heighten metabolic rate in both rodents and humans. Nonetheless, it remains unclarified whether thyroid hormones elicit adipose tissue energy expenditure exclusively through upregulating UCP1, or partially act via UCP1-independent mechanisms. The current project aims to investigate whether thyroid hormones activate adipose thermogenesis in UCP1-independnet manner and to examine the underlying molecular mechanisms. Based on our findings, we verified the adaptive thermogenic roles of thyroid hormone in UCP1 ablated white adipose tissue. Upon chronic cold exposure, I found that Ucp1 knockout (KO) mice exhibit higher levels of energy expenditure, which is principally attributed to the increased oxygen consumption in inguinal WAT (iWAT), supporting the existence of alternative thermogenic mechanisms in iWAT. Expression levels of type II iodothyronine deiodinase (Dio2) and intracellular level of T3 are significantly higher in iWAT lacking UCP1 compared to that in UCP1-expressed iWAT. In hypothyroid Ucp1 KO mice, the body temperature drops sharply when exposed to 6℃, suggesting that thyroid hormone is essential for UCP1-independent adaptive thermogenesis. Additionally, supplementation of T3 leads to an equal induction of energy dissipation in WT and UCP1-ablated mice, and causes notable loss of fat mass in obese Ucp1 KO mice housing at thermoneutral ambient, indicating that thyroid hormone is able to increase energy expenditure in WAT in addition to the canonical SNS-UCP1 cascade. To gain deeper insight into T3-regulated thermogenesis, I subjected iWAT from hypothyroid and hyperthyroid mice to RNA sequencing. Through pathway enrichment analysis of RNA-seq data and the following verification, sodium-potassium pumps and channels were markedly upregulated by T3 and cold stimuli at mRNA and protein expression levels in iWAT lacking UCP1. In vitro, I found that T3 treatment activates Atp1a1 and Atp1a2 in white adipocytes, accompanied by elevation of oxygen consumption. Moreover, T3-evoked oxygen consumption is significantly blocked by pharmacological inhibition of ATP-dependent sodium-potassium pumps, demonstrating that thyroid hormone dissipates energy by accelerating ion transport-related ATP consumption. On the other hand, I found that T3-induced expression of Atp1a1 and Atp1a2 is tissue-specific, which requires thyroid hormone receptors (TRs) and/or carbohydrate response-element binding protein (ChREBP). In white adipocytes, T3 potentiates expression of sodium-potassium pumps and ion leak channels, which establishes a futile cation transport circle to generate heat. Collectively, this study highlights that thyroid hormone induces adaptive thermogenesis in WAT through UCP1-independnet mechanism, in addition to its clasical sympathetic nervous system (SNS) /UCP1-related pathway.