Novel approaches to white adipose browning and beige adipose activation for the treatment of obesity
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Brown and beige fat are specialized adipose tissues found in almost all mammals that can increase energy expenditure and produce heat. Cold exposure and b3-adrenergic stimulation has been extensively shown to activate brown adipose tissue (BAT) in rodents, which promotes uncoupled respiration of glucose and lipid substrates via uncoupling protein 1 (UCP1). Prolonged stimulation can induce white adipose browning, which leads to the emergence of thermogenic cells within white fat depots, called beige adipocytes. The beige adipocyte possesses a unique molecular signature, yet shares several characteristics of brown adipocytes, including high mitochondrial content. When activated, beige fat can be induced to initiate a thermogenic transcriptional program similar to that of BAT. Recent human studies have identified brown and/or beige fat in the supraclavicular region using various radiation imaging modalities. This remarkable discovery has reinvigorated scientific interest in adipose browning and brown/beige fat activation as possible therapeutic targets for obesity. Like in rodents, several groups have previously tested the potential impact of cold exposure and b3-adrenergic agonism on BAT-mediated thermogenesis in humans. However, even though these approaches were shown to significantly increase energy expenditure and promote weight loss in obese individuals, they are not ideal clinical interventions. Cold exposure is uncomfortable and requires prolonged treatment, while b3-adrenergic agonists may lead to many adverse effects like cardiovascular problems. This thesis will evaluate the therapeutic potential and clinical relevance of alternative anti-obesity approaches that target adipose browning and beige adipose activation.