Thermogenesis and Fuel Selection During Cold Exposure: Tissue-Specific Metabolism and Cold-Acclimation.

Abstract

The focus of this thesis was to further elucidate the tissues and metabolic processes contributing to heat production during cold exposure, examine the interaction between the primary thermogenic organs and investigate the plasticity of these processes following a cold-acclimation protocol. The manuscripts contained within the thesis describe how this was accomplished. First, we began by examining the role of brown adipose tissue (BAT) in producing heat in adult humans. Prior to 2009, this tissue was considered metabolically irrelevant following infancy. However, our first manuscript showed that in fact this tissue can contribute to metabolic heat production during cold exposure but to an extent that varies from person to person, with some individuals relying predominantly on BAT to produce heat whereas others relied on shivering muscles. We then proceeded to examine the interaction and contribution of these two tissues in producing heat and clearing circulating substrates, such as glucose and fatty acids. In the process we also investigated the energy storing and dissipation relationship between white and brown adipose tissue. There were suggestions in the literature that perhaps the mechanisms that lead to white adipose tissue dysfunctions in obese and diabetic individuals may be shared with brown adipose tissue, explaining the apparent scarcity of this tissue in those populations. What was clear in this second manuscript, was that such a relationship is very plausible but, in addition, the thermogenic and substrate handling potential of skeletal muscle far exceeds the capacity from BAT and may be a more viable target to assist in the treatment of these metabolic diseases. The two final manuscripts focused on describing the potential for both BAT and skeletal muscle to change its phenotype in response to four weeks of daily cold exposure. The first of these two manuscripts investigated the plasticity of BAT and its subsequent effect on shivering and whole body energy metabolism, when exposed to a temperature that is slightly warmer than the temperature participants were acclimatized. Although BAT increased in volume and oxidative metabolism, its potential to alter whole body responses were not evident. Consequently, we explored the possibility that perhaps a colder thermal challenge was required in order to provoke the necessary response that demonstrates the thermogenic potential of this tissue. In this final manuscript, we found that even at colder temperatures, shivering intensity remained the same after a four week cold acclimation intervention, but that simply its onset and the skin temperature threshold to trigger detectable levels of shivering were shifted later in the acute cold exposure period. Interestingly, by taking muscle biopsy samples during these colder thermal challenges, we were able to identify that skeletal muscle had also altered its phenotype over the four weeks, by reducing the cold-induced mitochondrial uncoupling that was apparent in the non-acclimated participants. This suggested that perhaps the simultaneous changes that occurred in BAT and skeletal muscle were neutralized when examining whole-body measurements, which resulted in no detectable changes in whole body heat production following a four-week cold acclimation. What we discovered in the end was that, indeed, BAT is thermogenically relevant in adult humans and under mild cold conditions its thermogenic contribution compared to shivering muscles varies tremendously between individuals. Further, both BAT and skeletal muscle demonstrated tremendous plasticity as a result of daily cold exposure. However, what was also clear is that both the contribution of BAT thermogenesis to whole body heat production and the ability to clear circulating substrates is quite limited when compared to skeletal muscle. Combined, the findings from this thesis provided indications that BAT may play a more local thermoregulatory role and perhaps clear circulating substrates sufficiently to manage small amounts of substrates in circulation, but unlikely to be sufficiently potent to reverse the effects of diabetes and obesity, where excessive levels of substrates are present.