Mechanisms Driving Human Adipose Tissue Thermogenesis in vivo and its Clinical Applications in Metabolic Health

Abstract

For many years, adipose tissue (AT) was thought to be a tissue primarily responsible for cushioning and insulating organs. However, significant advances in knowledge have shown that AT is necessary for maintaining an optimal metabolic balance through paracrine and endocrine mechanisms. Because AT dysfunction is related with illnesses such as obesity and diabetes, it is vital to understand the mechanisms behind these pathologies to restore metabolic health. Beige AT is a unique form of fat that generates heat through uncoupling protein 1 (UCP1), has a dense neurovascular network, and is associated with enhanced metabolic health. Hence, particular emphasis has been made on unraveling the processes behind thermogenic activation and maintenance, as increasing thermogenic activity offers considerable potential for treating metabolic disorders. Activation of beige AT is dependent on norepinephrine release from sympathetic neurons upon physiological cues such as cold exposure. Studies have revealed a major role of monoamine oxidase a (MAOA)-mediated norepinephrine clearance in the maintenance of thermogenic AT. However, major limitations are still present with regards to the mechanisms of neurotransmitter clearance and their role in thermogenic regulation. The initial objective of this thesis is to evaluate the effect of human white and thermogenic adipocytes on the formation of a neurovascular network in order to maintain thermogenesis and whether MAOA plays a direct role in thermogenic control. We demonstrate that implanted human thermogenic adipocytes generate a more vascularized and innervated AT than non-thermogenic adipocytes. Additional findings revealed that MAOA is expressed in human adipocytes and that inhibiting MAOA promotes thermogenesis. The second objective of this thesis is to determine if hAdipoGel (hAG) - a decellularized AT matrix – enhances mesenchymal stem cell (MSC) proliferation and differentiation, as well as human adipocyte engraftment in vivo. We show that MSC can proliferate in hAG and differentiate effectively into white and thermogenic adipocytes. Additionally, when white adipocytes are implanted with hAG, they differentiate into a fully functioning fat graft capable of integrating with the host. Understanding the thermogenic processes of human AT, in combination with the use of a suitable decellularized matrix, can aid in the development of therapeutic treatments that boost thermogenic activity and hence metabolic health.