An obesogenic diet uncovers disparate changes in uncoupling protein 1 content and lipid synthesis and storage in rat brown adipose tissue

Brown adipose is a specialized organ rich in mitochondria and uncoupling protein 1 (UCP1). It is activated by the sympathetic nervous system resulting in a UCP1-dependent uncoupling of oxidative phosphorylation from ATP generation leading to the generation of heat (Cannon & Nedergaard, 2011). This has classically been shown to occur in rodents exposed to the cold and is one of the principal mechanisms of non-shivering thermogenesis that is engaged to maintain core body temperature. In addition to cold stress there is evidence that brown adipose tissue and UCP1 play a role in mediating diet-induced thermogenesis. In support of this, brown adipose tissue and UCP1 protein content are increased in rodents provided with an obesogenic diet (Wu et al., 2014), whereas the ablation of UCP1 in some (Feldmann et al., 2009), but not all (Dieckmann et al., 2022), studies potentiates weight gain in mice housed at thermoneutrality. Despite increases in UCP1 and brown adipose tissue mass in rodents fed high fat and sugar diets, increases in adiposity and the development of impaired lipid and glucose metabolism still occur, suggesting that expansion of brown adipose tissue/UCP1 is not sufficient to protect against these deleterious responses. Within this framework, in an article in this issue of The Journal of Physiology, Da Eira and colleagues (2023) set out to examine the underlying metabolic adaptations that occur within brown adipose tissue in response to the long-term consumption of an obesogenic diet. Consistent with what has been shown previously there was a robust expansion of brown adipose mass and increases in UCP1 protein content in rats fed a high fat and sugar diet. Despite large increases in UCP1, glucose and fat oxidation in isolated brown adipocytes were not increased, and depending upon the experimental conditions examined, were actually reduced. In parallel with this Da Eira et al. reported that the incorporation of glycerol and palmitate into triglyceride and the protein content of key enzymes involved in fatty acid re-esterification were increased in brown adipocytes from rats fed a high fat and sugar diet. While there have been a number of studies which have reported the ‘whitening’ of brown adipose tissue, the current work is noteworthy as the authors completed an extensive physiological assessment of the biochemical pathways mediating the metabolic fate of glucose and fatty acids in brown adipocytes. They provided evidence of a metabolic shift characterized by increases in fatty acid synthesis and storage in conditions of diet-induced obesity. The findings of this report raise several interesting points that warrant further discussion. First, what is/are the underlying signal(s) driving the increased synthesis and storage of fatty acids within brown adipose tissue from rats fed a high fat and sugar diet, and are these signals the same as those which are causing impairments in glucose and fatty acid oxidation? Second, how rapidly does brown adipose tissue metabolism shift in response to an obesogenic diet and does this correspond temporally to alterations in whole body energy balance and adipose tissue accretion? Lastly, does the disconnect between increases in UCP1 and glucose and fatty acid oxidation measured ex vivo hold when similar endpoints are measured in vivo? For instance, would brown adipose tissue activity measured by thermography and/or whole-body energy expenditure be reduced in rats fed a high fat and sugar diet when challenged with CL 316243, a β3 adrenergic agonist which activates brown adipose tissue? Although the current work by Da Eira et al. provides intriguing insight into brown adipose tissue metabolism in obesity, there are several caveats with this current investigation that need to be acknowledged. First, the experiments were completed at room temperature, which is below the thermoneutral zone for rats. This represents a degree of thermal stress and consequently leads to the engagement of heat producing/conserving processes such as brown adipose tissue-mediated, non-shivering thermogenesis (Cannon & Nedergaard, 2011). Given this, it remains to be determined if the same alterations in brown adipose tissue metabolism in rats fed a high fat and sugar diet would be seen in animals housed at thermoneutrality. An additional consideration is that Da Eira et al. only studied male rats. This is an important point as the ‘whitening’ of visceral and subcutaneous adipose tissue in response to obesogenic diets, at least in mice, is more pronounced in males compared to females (Dobner et al., 2017). Thus, it would be interesting to examine if similar sexual dimorphism in the endpoints measured by Da Eira et al. exist in brown adipose tissue/adipocytes. Even with these limitations in mind the work by Da Eira and associates makes an important contribution to the field and highlights previously unappreciated parallel changes between increases in UCP1 and apparent enhancements of lipid synthesis and storage. Teasing out the relationship between these apparent disparate processes, as well as delving into the questions highlighted above, should provide exciting avenues for further research elucidating the role of altered brown adipose tissue metabolism in the pathophysiology of obesity and the related metabolic complications.