Our Objective...
Here, we will be focusing on non-exercise, non-shivering thermogenesis. More specifically, we will be exploring how UCP1 in BAT contributes to thermogenesis in hibernating mammals and humans, as well as its clinical application to obesity.
How does Uncoupling of the ETC to Oxidative Phosphorylation Lead to Thermogenesis in Mammals?
In general, ATP production is carefully regulated by the coupling of the electron transport chain (ETC) to oxidative phosphorylation in the inner mitochondrial membrane. Reducing equivalents NADH and FADH2 from the tricarboxylic acid cycle (TCA) and β-oxidation are reduced by the ETC, and protons (H+) are pumped into the matrix, generating a proton gradient. Protons are then converted into ATP by F1F0-ATP synthase. In response to extreme cold temperatures, thermogenesis in hibernating mammals is the result of the uncoupling of the ETC from oxidative phosphorylation.
|
How is Thermogenesis Initated?
Thermogenesis is initiated through the body’s “fight-or-flight” mechanism which is activated upon the release of norepinephrine by the sympathetic nervous system (SNS). Norepinephrine binds to β3-adrenergic receptors (βAR) on the cell membrane, activating GTP-binding protein Gs and inducing the production of cyclic adenosine monophosphate (cAMP) by adenylate cyclase (AC). cAMP activates cAMP-dependent protein kinase (PKA), which in turn phosphorylates and activates lipolysis in BAT by hormone-sensitive lipase (HSL). LCFAs can be produced by beta-oxidation to activate the UCP1-mediated proton conductance pathway. This pathway, known as the βAR-cAMP-PKA pathway, activates UCP1 and generates heat for hibernation and arousal.
Case Study: How is Thermogenesis Different in Cold-Acclimated vs. Hibernating Richardson's Ground Squirrels?
According to a study by Milner et. al (1989) on the thermogenic activity and capacity of BAT in the hibernation cycle of Richardson's ground squirrels, hibernating squirrels were examined during post-hibernation, hibernation and arousal.
What Happens in Hibernating Squirrels?
By comparing the hibernation cycle of the normal ground squirrels, researchers found that the total BAT and total mitochondrial content increases in preparation for hibernation. As seen in Table 1, squirrels in hibernation were considerably heavier than post-hibernating squirrels and had significantly increased BAT content, tissue protein and cytochrome-c oxidase activity (an indicator of mitochondrial content). However, there were no significant differences between hibernating and aroused squirrels for these indicators. Together, these results suggest that preparation for hibernation is associated with a major increase in the mitochondrial content in BAT as well as large increases in BAT mass due to pre-hibernation fattening.
What Happens in Cold-Acclimated Squirrels?
Similarly, comparison of cold-acclimated squirrels (capable of adaptive thermogenesis in cold environments) to post-hibernating squirrels displayed similar results to the hibernating and arousing groups. Cold-acclimated squirrels had increased BAT levels, tissue protein and cytochrome-c oxidase activity compared to the post-hibernating group (Table 1). However, unlike the hibernating and arousing groups, there was no significant change in the body weight of cold-acclimated and post-hibernating squirrels. These results indicate that the cold acclimatization of Richardson's ground squirrels also increases BAT and mitochondrial content, but these changes took place without a major alteration in body weight.
What About Differences in UCP1?
|
Figure 1. Specific UCP1 mitochondrial protein in BAT of Richardson's ground squirrel. Mitochondrial UCP1 concentrations are similar for post-hibernating, hibernating and arousing squirrels with the exception of cold-acclimated squirrels.
|