• 2019-07
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  • 2019-09
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  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • The mitochondrial defects in BAT


    The mitochondrial defects in BAT of MTERF4-FAT-KO mice are reminiscent of those found in heart of cardiac-specific MTERF4 knockout mice, which show reduced assembly and activity of OxPhos complexes I, III, IV and V, as well as low content of mtDNA-encoded proteins and reduced levels of some nDNA-encoded subunits [22]. The pathophysiological result of the loss of MTERF4 in heart is the development of a severe cardiomyopathy that leads to premature death around 21 weeks of age, as a direct consequence of the disruption of proper mitochondrial function. A major difference between the cardiac- and our adipose-specific knockout models lies in the transcriptional response to impaired mitochondrial function. Indeed, in heart of cardiac-specific knockout mice, a noticeable increase in the levels mtDNA-encoded RNAs was found [22], suggesting the activation of a mitochondrial biogenic response aimed at compensating mitochondrial dysfunction and maintaining cardiac function. In this line, a dramatic increase mitochondrial mass was observed in Nutlin-3 of heart-specific MTERF4-KO mice, which show aberrant mitochondria arranged in a disorganized manner within the cardiac muscle fibers. However, the lack of such compensatory mitochondriogenic response in BAT, despite the severe defect in its oxidative function, together with the fact that MTERF4-FAT-KO mice maintain normal energy expenditure and body temperature when housed at 21 °C suggest that mice can adapt to defective BAT thermogenesis by recruiting other thermogenic mechanisms that overtake the function of inactive BAT. Therefore, whereas a mitochondriogenic response in heart of cardiac-specific MTERF4-KO mice is absolutely required as an attempt to maintain heart function at any Nutlin-3 cost, such response might be dispensable in BAT, since brown adipocyte thermogenesis could be substituted by alternative thermogenic mechanisms [36]. Thus, under normal housing conditions (21 °C), the mitochondria with smaller cristae and reduced OxPhos complexes content of MTERF4-FAT-KO mice appear sufficient to sustain viable brown adipocytes. However, when animals are exposed to cold, the newly recruited thermogenic mechanisms are insufficient to maintain the production of heat required to maintain body temperature and MTERF4-FAT-KO mice get into hypothermia. The MTERF4-FAT-KO phenotype would be similar to that observed in UCP1 knockout mice, which, despite of exhibiting impaired BAT non-shivering adaptive thermogenesis due to the lack of UCP1, they adapt to low temperatures by increasing shivering [33]. The recruitment of other recently described processes with thermogenic potential, such as creatine futile cycle [37] or the generation of endogenous n‑acyl amino acids with uncoupling properties [38] in MTERF4-FAT-KO mice cannot be disregarded and would deserve further investigation. Moreover, it would be interesting to investigate if long term adaptation to mildly cold temperatures is sufficient to mount the mitochondriogenic response that was not observed under the temperature conditions used in the present study. Owing to its high oxidative capacity, BAT may exert a notable influence on energy balance [39,40]. Lower BAT mass and activity in adult humans is associated with increased body mass index and blood glucose levels [8,9], suggesting that impaired BAT oxidative function may predispose to the development of obesity and glucose metabolism disturbances. Surprisingly, MTERF4-FAT-KO mice do not gain more weight than their Wt littermates nor they exhibit any alteration in glucose homeostasis, even when fed an obesogenic diet. The lack of differences in body weight between Wt and MTERF4-FAT-KO mice clearly indicate that whole body energy balance is preserved in mice lacking MTERF4, despite the severe impairment in BAT oxidative function observed. This is consistent with the absence of differences in energy expenditure and food intake between Wt and MTERF4-FAT-KO mice. These, somehow, surprising findings are in line with the results of other studies in rodent models devoid of genes like Ucp1 [32], Hdac3 [41] or Cpt2 [42] specifically in adipocytes. All these mouse models are characterized by deficient thermogenesis and exacerbated cold sensitivity, but none of them become obese, even if fed a high fat diet. Altogether, these studies seem to undermine the contribution of BAT to whole body energy expenditure. However, they are compatible with recent studies that describe the recruitment of alternative thermogenic mechanisms aimed at maintaining body temperature under standard housing conditions in mice devoid of UCP1-dependent BAT non-shivering thermogenesis. As mentioned above, different futile cycles or alternative thermogenic mechanisms that contribute to energy expenditure and heat production have been described in other tissues [37,38,43,44]. Nevertheless, the contribution of these UCP1-independent thermogenic mechanisms to whole body energy balance has not been explored in humans.