Regardless of whether lack of basal thermogenic activity in
Regardless of whether lack of basal thermogenic activity in brown adipocytes is sufficient to bring about a deleterious metabolic phenotype, many studies in rodents support the notion that enhanced activation of BAT and browning of WAT greatly influence Y-27632 balance and prevent obesity and obesity-related metabolic diseases, like insulin resistance or type 2 diabetes [7,50]. In humans, evidence that boosted activity of BAT has positive metabolic effects come from patients with hibernomas or pheochromocytomes, who show abnormally increased BAT mass and activity in correlation with reduced body weight [51,52]. Also, BAT activation by cold exposure in adult humans has been shown to significantly increase energy expenditure and to improve whole body insulin sensitivity [53,54]. Therefore, brown and beige adipocytes have been viewed as an appealing target for the treatment of metabolic diseases. Our findings that Wt mice but not MTERF4-FAT-KO fed a high fat diet respond to treatment with the β3-receptor agonist CL316,243 by increasing oxygen consumption and improving glucose homeostasis are in full support of this idea. Again, the blunted response to the treatment with CL316,243 observed in MTERF4-FAT-KO is not the result of impaired UCP1 expression in BAT, since both Wt and MTERF4-FAT-KO mice exhibit similar levels of the protein in response to adrenergic stimulation. Similarly, the browning capacity of WAT, as judged by the induction of UCP1 protein, is preserved in MTERF4-FAT-KO mice. Remarkably, the similar glucose uptake capacity exhibited by BAT of Wt and MTERF4-FAT-KO mice when treated with a β3-receptor agonist strongly suggests that the blunted improvement in glucose homeostasis exhibited by mice lacking MTERF4 is not due differential glucose uptake capacity in BAT. While glucose uptake has been often used as readout of BAT thermogenesis, our results are in line with recent reports that demonstrate a dissociation between adrenergically-induced glucose uptake and thermogenesis . The lack of improvement in glucose homeostasis and reduction in body weight clearly seems to be the result of the incapacity of adrenergic stimulation by β3-adrenergic receptor specific agonists to increase energy expenditure in brown and beige adipocytes. Although we did not measure it, the glucose uptake attributable to beige adipocytes is not expected to be different between Wt and MTERF4-FAT-KO mice, since both beige and brown adipocytes, despite their different ontogenic origin, similarly respond to adrenergic stimulation by activating UCP1-depedent thermogenesis . Still, given the reduced mitochondrial OxPhos protein content in WAT as a result of the lack of MTERF4, a potential contribution of white adipocytes to the differential metabolic response to adrenergic stimulation cannot be totally ruled out. Our findings are similar to those reported in a recent study using mice simultaneously devoid of ERRα and ERRγ, two orphan hormone nuclear receptors that redundantly regulate mitochondrial biogenesis in brown/beige adipocytes. ERRα/γ adipose-specific double knockout exhibit impaired thermogenesis and are refractory to the metabolic effects of adrenergic stimulation. As a result, they do not improve glucose homeostasis nor they reduced body weight in response to CL316,243 to the same extent as their Wt counterparts . Altogether, these findings strongly suggest that pharmacological activation of brown/beige adipocytes by the use of sympathomimetics would be sufficient to revert diet-induced insulin resistance in humans. However, the undesirable cardiovascular side effects (i.e. rise in blood pressure and heart rate) associated with the therapeutic doses of adrenergic receptor agonists used in the clinical practice preclude their use in obese and diabetic patients [56,57]. In this regard, several new molecules, including fibroblast growth factor 21, natriuretic peptides, bone morphogenic proteins or capsinoids, with the capacity to recruit and activate brown adipocytes have been identified, but their therapeutic potential remain to be defined (reviewed in [7,58]).