Resumen de Regulation of brown adipose tissue metabolism by tp53inp2
Overweight and obesity have increased dramatically during recent decades becoming a major health problem for which therapeutic options are limited. Thus, there is an urgent need to develop new safe pharmacological therapies. Obesity results from the positive imbalance resulting from the increase of energy intake and/or decrease in energy expenditure, the latter consequence of impaired processes involved in basal metabolism, adaptive thermogenesis or associated with sedentary behaviour. The excess of energy is preferentially stored in white adipose tissue (WAT) within unilocular adipocytes. Another type of adipose tissue, the brown adipose tissue (BAT), is in charge of utilizing nutrients to produce heat in an attempt to maintain body temperature through non-shivering adaptive thermogenesis. Brown adipocytes are multilocular with many lipid droplets and mitochondria that express uncoupling protein-1 (UCP1), the final effector of heat dissipation. Upon adrenergic stimulation induced either by cold or by diet, the rise in intracellular cyclic AMP levels (cAMP) results in UCP1 activation increasing lipid oxidation uncoupled from ATP production. Functional BAT depots have recently been detected in lean adult humans that can be activated by cold exposure. Of relevance, human BAT activity correlates with lower body mass index and improved glycemia, indicating that strategies that could increase BAT mass and/or its activation could become promising targets to combat obesity and its metabolic complications. Tumour protein p53-inducible nuclear protein 2 (TP53INP2) promotes autophagy and stimulates a variety of nuclear hormone receptors, such as ecdysone receptors in flies, and thyroid hormone receptors, glucocorticoid receptors and PPAR receptors in mammalian cells. TP53INP2 is also a negative regulator of white adipogenesis through activation of TCF transcription factors. The transcription factor PPARγ plays a key role in the regulation of BAT thermogenesis, as well as in brown adipogenesis. However, the factors that modulate PPARγ activity in brown adipocytes are largely unknown. Here we document that the bifunctional protein TP53INP2 is a major regulator of BAT function and that its action is mediated by the regulation of PPARγ activity. TP53INP2 was upregulated under conditions of stimulated BAT thermogenesis, such as under low temperature or a high-fat diet. TP53INP2 deficiency reduced brown adipogenesis in cultured cells, and in vivo TP53INP2 ablation in Myf5+ precursor cells caused the dysregulation of BAT gene expression and enhanced lipid droplet accumulation in brown adipocytes. As a result, TP53INP2 depletion decreased BAT-specific thermogenic capacity, leading to positive energy balance and obesity. Furthermore, TP53INP2 loss-of-function in adult mice revealed that the protein is required for the maintenance of the differentiation state of brown adipocytes. Microarray gene expression profiling showed that the lack of TP53INP2 in BAT is linked to a reduced PPAR signalling pathway. In keeping with this, PPARγ activity was markedly decreased in TP53INP2 knockout brown preadipocytes. Under conditions of TP53INP2 deficiency, PPARγ proteasomal degradation was also impaired and this transcription factor showed a lower ubiquitination. Moreover, chronic exposure to the ligand rosiglitazone rescued brown adipogenesis. In all, we have identified a novel regulator of PPARγ activity and BAT metabolism. The expression of this regulator in BAT is induced under conditions of active thermogenesis, and its repression leads to energy imbalance, reduced thermogenesis and obesity.
