Integrating Thyroid Hormone Signaling in Hypothalamic Control of Metabolism: Crosstalk Between Nuclear Receptors

Abstract

The obesity epidemic is well recognized as a significant global health issue. A better understanding of the energy homeostasis mechanisms could help to identify promising anti-obesity therapeutic strategies. It is well established that the hypothalamus plays a pivotal role governing energy balance. The hypothalamus consists of tightly interconnected and specialized neurons that permit the sensing and integration of several peripheral inputs, including metabolic and hormonal signals for an appropriate physiological response. Current evidence shows that thyroid hormones (THs) constitute one of the key endocrine factors governing the regulation and the integration of metabolic homeostasis at the hypothalamic level. THs modulate numerous genes involved in the central control of metabolism, as TRH (Thyrotropin-Releasing Hormone) and MC4R (Melanocortin 4 Receptor). THs act through their interaction with thyroid hormone receptors (TRs). Interestingly, TH signaling, especially regarding metabolic regulations, involves TRs crosstalk with other metabolically linked nuclear receptors (NRs) including PPAR (Peroxisome proliferator-activated receptor) and LXR (Liver X receptor). In this review, we will summarize current knowledge on the important role of THs integration of metabolic pathways in the central regulation of metabolism. Particularly, we will shed light on the crosstalk between TRs and other NRs in controlling energy homeostasis. This could be an important track for the development of attractive therapeutic compounds.

The Role of the Thyroid Axis in Fish

“…In mammals, the thyroid axis regulates food intake, body weight (309) and metabolic/nutrient homeostasis (310). The thyroid axis can influence feeding via the actions of TRH and THs in the brain, THs in the periphery, and also be influenced by endocrine appetite-regulating signals (e.g., NPY, leptin).…”

Thyroid hormones in diabetes, cancer, and aging

“…Upon ligand binding, THRs assemble into a co‐activator complex with histone acetyltransferase activity that is recruited to stimulate transcription (Lonard & O'Malley, 2007; Perissi et al, 2010). Moreover, THR interacts with other nuclear hormone receptors, such as peroxisome proliferator‐activated receptors, retinoid X receptors, retinoic acid receptors, and liver X receptors that allow binding to a wide repertoire of nucleotide sequences that contribute to regulate different metabolic pathways, including cholesterol, glucose, and fatty acid metabolism in different tissues (Brent, 2012; Kouidhi & Clerget‐Froidevaux, 2018). In addition, THs also modulate molecular pathways via protein–protein interactions such as PI3 K‐AKT‐FOXO1 and mTOR‐p70S6 K signaling, which further modulate transcription (Cao et al, 2005; Davis et al, 2016; Flamant et al, 2017; Mullur et al, 2014).…”

MC4R Variant rs17782313 Associates With Increased Levels of DNAJC27, Ghrelin, and Visfatin and Correlates With Obesity and Hypertension in a Kuwaiti Cohort

“…The overexpression of DNAJC27 in HEK-MC4R cells reduced the efficacy of the MC4Rmediated formation of cAMP by two MC4R agonists, NDP-α-MSH and setmelanotide. Previous studies have reported that the activity of MC4R is a key modulator of food intake; stimulating MC4R induced satiety whereas blocking MC4R increased the appetite (1,3,8). Furthermore, loss-of-function genetic variants of MC4R are associated with obesity whereas gain-of-function genetic variants are protective against obesity (22).…”

“…Conversely, AgRP neurons project into the PVH releasing AgRP, which blocks MC4R. This results in the activation of appetite and an increase in food intake (1,3,8).…”