Turn up and Burn up: Aerobic Exercise Training as a Strategy to Preserve Non-Shivering Thermogenesis on an Obesogenic Diet

With positive energy balance adipose tissue hypertrophies and contributes to negative health outcomes, such as metabolic syndrome. However, white and brown adipose tissue (BAT) have divergent effects on health. While excessive white adipose is associated with negative health outcomes, BAT contributes to energy dissipation and attenuated weight gain. Specifically, BAT contains uncoupling protein-1 (UCP-1) which, when triggered by the release of norepinephrine, uncouples ATP synthase, causing hydrogen ions to leak across the inner mitochondrial membrane, resulting in non-shivering thermogenesis (Da Eira et al., 2023). The existing literature suggests non-shivering thermogenesis through BAT is insufficient to prevent weight gain (i.e., the current obesity epidemic) or even suppressed in the context of obesity. For example, compared to lean young males, young males with obesity have less than 40% of the activation of BAT after cold exposure, despite having approximately twice the volume of BAT (Leitner et al., 2017). Therefore, in a recent Journal of Physiology article, Da Eira et al (Da Eira et al., 2023) sought to examine mechanistic changes leading to impaired diet-induced thermogenesis in BAT in the context of an obesogenic diet. Da Eira et al. fed male albino Wistar rats either standard chow (SC; Control) or high-fat sucrose-enriched (HFS) diet ad libitum for eight weeks. The rats were anesthetized after the feeding trials and tissues were harvested for the experiments of the present study.

The research team measured glucose uptake, lactate production, and tissue morphology of the adipose tissue. Transcription and translation of specific proteins of interest (i.e. peroxisome proliferator-activated receptor γ coactivator 1α [PGC-1α], carnitine palimtoyltransferase 1β [CPT-1β], UCP-1, CD36, and lipoprotein lipase [LPL]) were measured using quantitative polymerase chain reactions and western blotting. Consistent with previous human data (Leitner et al., 2017), HFS-fed rats gained more weight, exhibited greater adiposity (subcutaneous inguinal and epididymal fat pads), and greater mass of BAT (interscapular and aortic BAT). Within BAT, there was increased expression of thermogenic proteins PGC-1α (an oxidative phosphorylation protein), CPT-1β (fatty acid transporter responsible in skeletal muscle mitochondria), in response to the HFS diet. Increased expression of thermogenic proteins indicates greater potential for thermogenesis however, uncoupled glucose and fatty acid oxidation were reduced after the HFS condition. Exposure to the HFS condition also resulted in increased glucose uptake transporter 1 (GLUT1) expression and increased basal and insulin stimulated glucose uptake in BAT adipocytes. Additionally, several mechanistic changes indicating greater potential triacylglycerol synthesis also occurred under the HFS condition. For example, glycerol was incorporated into lipids and palmitate was incorporated into triacylglycerol at significantly greater rates. Upregulation of CD36 (cell membrane fatty acid transporter) and LPL (cleaves esterified fatty acids from chylomicrons circulating in the blood stream) indicated increased potential for fatty acid absorption into cells. Furthermore, glycerol release (a proxy measure of triacylglycerol lipolysis) and adipose triacylglycerol lipase (the first enzymatic step of lipolysis) were decreased, while PEPCK (converts pyruvate into phosphorylated glycerol) and glycerol kinase (phosphorylates glycerol) were increased in the HFS condition. Collectively, these data suggest that HFS resulted in BAT downregulating lipolysis and upregulating enzymes responsible for the esterification of triacylglycerol indicating that BAT adipocytes from HFS-fed rats are storing fatty acids as triacylglycerol rather than oxidizing fatty acids for thermogenesis. Interestingly, BAT β3-adrenergic receptor expression was upregulated in the HFS rats. In isolation, this finding would suggest that norepinephrine would have greater effects on the HFS BAT adipocytes, but the increased β3-adrenergic receptor expression could also be a compensatory response due to decreased activity (i.e., desensitization). Additionally, the BAT from HFS rats exhibited reduced concentrations of tyrosine hydroxylase (rate-limiting enzyme of catecholamine, particularly epinephrine, synthesis).

When approaching the application of these findings to human and various patient populations, it is important to note that BAT volume and activity play much smaller roles in metabolism and energy balance in humans than rodents. However, considering that the current obesity epidemic largely results from small, but chronic caloric surpluses, efforts to increase BAT activity in humans could play a role in maintaining metabolic health in the context of obesogenic diets. In fact, Da Eira et al demonstrated that the HSF diet upregulated fatty acid transporters and the enzymes responsible for the induction of lipolysis and thermogenesis, indicating that the BAT should function as phenotypically expected. Yet, following HFS, the BAT adipocytes functioned similarly to white adipocytes and stored substrates as triacylglycerol rather than using available lipids for thermogenesis (Da Eira et al., 2023). This is important for understanding the molecular phenotypes associated with obesity and other metabolic diseases, as these mechanisms are taken for granted in healthy populations and may need specific attention in certain clinical populations.

As exercise physiologists, we are particularly interested in the role exercise may play in increasing BAT activity (Carpentier et al., 2018). In particular, Fu et al (Fu et al., 2021) demonstrated that after 8 weeks of an obesogenic diet, a 4 week aerobic exercise intervention lead to decreased expression of genes associated with regulation and action of apoptosis and increased expression of genes associated with glucose metabolism, lipid biosynthesis, and steroid utilization in BAT of exercised mice compared to the BAT of the obese, control mice (Fu et al., 2021). In addition to these findings, Fu et al observed increases in BAT activation in the exercised mice resultant from downstream effects of vascular endothelial growth factor on BAT activation through the upregulation of cyclooxygenase 2 which increased UCP-1 activity (Fu et al., 2021), suggesting that in addition to the multifaceted effects exercise has on metabolic health, it may also lead to a browning of adipose tissue. Aerobic endurance exercise increases irisin and fibroblast growth factor 21 secretion, which have been shown to increase BAT metabolic activity (Carpentier et al., 2018). Exercise also increases activity and abundance of BAT thermogenic proteins such as PGC-1α and LPL and substrate translocase proteins like CD36. Interestingly, these proteins were also upregulated in response to the HSF diet and present potential pathways in which training adaptations may increase BAT thermogenic potential. However, while the increase in these proteins and thermogenic potential did not directly translate to increased BAT thermogenesis, the results of this study suggest that SNA, which is upregulated during exercise, may mediate the disconnect between BAT thermogenic potential and actual thermogenesis (Da Eira et al., 2023).

In conjunction to the benefits of exercise, another promising mechanism could be that exercise transiently increases BAT activity by increased sympathetic outflow (Wahrenberg et al., 1987) . Specifically, the findings by Da Eira et al are interesting to our group because of the observed impact of the HFS diet on the sympathetic nervous activity (SNA) on adipose tissue. We found the upregulation of β3-adrenergic receptors in BAT in response to the HFS exceptionally intriguing. It is thought that increased β3-adrenergic receptor density/activity should increase sympathetic transduction to effector organs. However, downregulation of tyrosine hydroxylase may negate any of the rescuing effects offered by increasing β3-adrenergic receptor density on brown adipocytes. Though no direct sympathetic recordings were done in this study, perhaps other physiological factors played a role between groups and could help explain the present findings. One factor we have identified was that micronutrient imbalance, due to potential large differences in macronutrient profiles, may have influenced sympathetic drive. Specifically, differences in chronic sodium consumption influences water consumption, thus effecting blood volume which has long-term impacts on SNA activity.

In summary, exercise serves as a hermetic stressor that could improve thermogenic potential of BAT into thermogenesis in addition to contributing modestly to increased total energy expenditure. Furthermore, resistance-based exercise may contribute to nutrient partitioning whereby excess substrate may be utilized for protein synthesis and skeletal muscle hypertrophy as opposed to triacylglycerol synthesis and adipose hypertrophy. These adaptations to exercise could present potential additive effects by increasing both the thermogenic potential and activity of BAT and reduced energy overload. Consequently, these stimuli may offer therapeutic effects to combat metabolic dysfunction by increasing energy expenditure of BAT in the context of obesogenic diets. It is worth noting that literature in rodents suggests beneficial effects of exercise on BAT activity. Yet, when applying this in humans there are a plethora of exercise prescription variables that could differentially impact BAT activity (i.e. intensity, type, and duration) that still requires investigation. Furthermore, the present study has generated several interesting future directions including investigating the potential sex differences in β3-adrenergic receptor density and activity in BAT due to the influence estrogen is thought to exert on β-adrenergic receptor density. Additionally, investigating whether the HSF diet would have similar effects in the female rats could determine the potential protective properties of circulating sex hormones on β3-adrenergic receptor density and sympathetic activity in response to an obesogenic diet. Another interesting future direction would include normalizing BAT to body mass as done by Fu et al (Fu et al., 2021), which may assist in further elucidating how BAT is hypertrophied in comparison to total fat mass. Moreover, investigating how different modes of exercise influence BAT activity despite an obesogenic diet may provide mechanistic insight into specific therapies for clinical populations.