Transient Receptor Potential (TRP) based polypharmacological combination stimulates energy expending phenotype to reverse HFD-induced obesity in mice

Obesity is a worldwide epidemic leading to decreased quality of life, higher medical expenses and significant morbidity. Enhancing energy expenditure and substrate utilization in adipose tissues through dietary constituents and polypharmacological approaches is gaining importance for the prevention and therapeutics of obesity. An important factor in this regard is Transient Receptor Potential (TRP) channel modulation and resultant activation of “brite” phenotype. Various dietary TRP channel agonists like capsaicin (TRPV1), cinnamaldehyde (TRPA1), and menthol (TRPM8) have shown anti-obesity effects, individually and in combination. We aimed to determine the therapeutic potential of such combination of sub-effective doses of these agents against diet-induced obesity, and explore the involved cellular processes. The combination of sub-effective doses of capsaicin, cinnamaldehyde and menthol induced “brite” phenotype in differentiating 3T3-L1 cells and subcutaneous white adipose tissue of HFD-fed obese mice. The intervention prevented adipose tissue hypertrophy and weight gain, enhanced the thermogenic potential, mitochondrial biogenesis and overall activation of brown adipose tissue. These changes observed in vitro as well as in vivo, were linked to increased phosphorylation of kinases, AMPK and ERK. In the liver, the combination treatment enhanced insulin sensitivity, improved gluconeogenic potential and lipolysis, prevented fatty acid accumulation and enhanced glucose utilization. We report on the discovery of therapeutic potential of TRP-based dietary triagonist combination against HFD-induced abnormalities in metabolic tissues. Our findings indicate that a common central mechanism may affect multiple peripheral tissues. This study opens up avenues of development of therapeutic functional foods for obesity. In 3T3L1 cells the triagonist combination reduced lipid accumulation and adipocyte differentiation from preadipocytes. This also promotes effective glucose utilization along with enhanced thermogenic activities mediated through intracellular calcium uptake leading to phosphorylation on AMPK and enhanced UCP-1 expression. This possibly could be due to increased mitochondrial biogenesis and its activities. In in-vivo settings as a therapeutic approach in HFD-induced mice it promotes browning of white adipose tissue and enhanced the activity of brown adipose tissue by factors modulating the lipid metabolism such as PPAR-γ, PGC1α, PRDM16, SIRT-1 which mecha