LAUSR

(2018) Novel therapies are required to address the pandemics of obesity and type 2 diabetes mellitus (T2DM). Stimulating thermogenesis in brown adipose tissue has received a lot of research attention as a potential avenue for developing these new therapies. Now, a new paper has demonstrated that targeting a cold receptor and a nicotinic receptor reverses dietinduced obesity (DIO) and glucose intolerance in mice. “Inspired by the environmental stressors, cold exposure and smoking, we explored the possibility of utilizing the metabolic benefits of these environmental stimuli using pharmacological approaches; targeting a cold-sensitive calcium channel (TRPM8) and the neuronal acetylcholine receptor subunit β-4 (CHRNB4),” explains author Christoffer Clemmensen. First, the researchers administered icilin (an agonist of TRPM8) to mice with DIO. These mice lost weight, which was found to be the result of enhanced energy expenditure through increased thermogenesis rather than increases in activity levels or decreases in food intake. Next, mice with DIO were treated with dimethylphenylpiperazinium (DMPP; an agonist of the nicotinic receptor CHRNB4). These mice also lost weight, but this result was found to be due to suppressed food intake. Importantly, treatment with DMPP also improved diet-induced glucose intolerance, even at doses that had very little effect on body weight. Following these promising results with the two monotherapies, the researchers treated mice that had DIO with icilin (5 mg/kg) and DMPP (10 mg/kg). Mice that received this combination therapy lost weight as a result of reduced food intake and increased energy expenditure. Furthermore, the co-treatment also improved non-alcoholic steatohepatitis and non-alcoholic fatty liver disease. Of note, the metabolic effects of the combined therapy were greater than the sum of the effects of the two monotherapies. The melanocortin pathway is known to be involved in glucose metabolism, leading the authors to speculate that this pathway could also explain the effects of the icilin and DMPP co-treatment. Indeed, the treatment was ineffective in obese mice that were deficient for the melanocortin 4 receptor, which suggests that the melanocortin pathway is required for the beneficial effects of the co-treatment. “We are currently in the process of further optimizing this novel pharmacotherapy,” says author Matthias Tschöp. The investigators also plan to test the combined therapy in other species, and hope to design a method that can act on both pathways using a single compound.