Brown adipose tissue (BAT) regulates body temperature through non-shivering thermogenesis. Browning, the induction of a brown adipose-like phenotype in white adipose tissue (WAT), increases β-oxidation, mitochondrial biogenesis and thermogenesis(1). Brown adipocyte-like cells (beige adipocytes) are interspersed within WAT, and alter systemic energy balance with anti-obesity effects. In humans, BAT quantity correlates with decreased risk of diabetes and cardiovascular disease. However, BAT and beige adipose tissue can affect systemic energy balance independently of thermogenesis. Brown and beige adipose tissue thermogenesis leads to propagation of thermogenesis in surrounding and distal WAT and increases fat oxidation in skeletal muscle. This suggests brown/beige adipocytes influence systemic metabolism through interorgan signals in the adipocyte secretome. The nature of these signals is incompletely defined.
Metabolites were considered intermediates or end-products of metabolism, passive participants changed by metabolic processes. There is emerging evidence of metabolites, which function to mediate cellular signalling and interorgan crosstalk, regulating local metabolism and systemic physiology. These signals have been termed metabokines. Developing contemporaneously with the new appreciation of the complexity of tissue-crosstalk mediated by metabolites is an understanding that bioactive lipids also have a key role in the communication between cells, organs and tissues. These bioactive lipids have been termed lipokines. There is impetus to uncover novel metabokine signalling axes to understand how these are perturbed in metabolic diseases and determine their utility as therapeutic targets.
Our research has defined discrete brown/beige adipose tissue-derived metabokine and lipokine-mediated signalling axes that drive enhanced fatty acid oxidation in skeletal muscle. Reciprocally, we have identified an exercise-induced skeletal muscle-derived metabokine that drives adipose tissue browning. Here we will provide an overview of our research identifying novel metabokine signals:
1) Monocarboxylic acids secreted from thermogenic adipose tissue, which induce a thermogenic phenotype in white adipose tissue and oxidative energy metabolism in skeletal muscle to reduce adiposity, increase energy expenditure and improve glucose and insulin homeostasis in models of obesity and diabetes.
2) A lysophosphatidylcholine that functions as a BAT/beige adipocyte interorgan lipokine increasing fat oxidation in muscle and adipose tissue to increase systemic energy expenditure with anti-obesity effects
3) A bioactive non-protein β-aminoacid secreted from skeletal muscle during exercise, which induces adipose tissue thermogenesis and liver β-oxidation.
Our discoveries further our understanding of metabokine and lipokine mediated adipose tissue – skeletal muscle crosstalk, and the potential therapeutic role that these metabokines/lipokines may have to treat obesity and related cardiometabolic diseases.