Piperine’s mitigation of obesity and diabetes can be explained by its up-regulation of the metabolic rate of resting muscle

Abstract

We identify a target for treating obesity and type 2 diabetes, the consumption of calories by an increase in the metabolic rate of resting skeletal muscle. The metabolic rate of skeletal muscle can be increased by shifting myosin heads from the super-relaxed state (SRX), with a low ATPase activity, to a disordered relaxed state (DRX), with a higher ATPase activity. The shift of myosin heads was detected by a change in fluorescent intensity of a probe attached to the myosin regulatory light chain in skinned skeletal fibers, allowing us to perform a highthroughput screen of 2,128 compounds. The screen identified one compound, which destabilized the super-relaxed state, piperine (the main alkaloid component of black pepper). Destabilization of the SRX by piperine was confirmed by single-nucleotide turnover measurements. The effect was only observed in fast twitch skeletal fibers and not in slow twitch fibers or cardiac tissues. Piperine increased ATPase activity of skinned relaxed fibers by 66 ± 15%. The K d was ∼2 μM. Piperine had little effect on the mechanics of either fully active or resting muscle fibers. Previous work has shown that piperine can mitigate both obesity and type 2 diabetes in rodent models of these conditions. We propose that the increase in resting muscle metabolism contributes to these positive effects. The results described here show that up-regulation of resting muscle metabolism could treat obesity and type 2 diabetes and that piperine would provide a useful lead compound for the development of these therapies.myosin | fluorescence | skeletal muscle | super-relaxed state | obesity A n epidemic of obesity and type 2 diabetes is currently affecting a large fraction of the world population (1, 2). This is primarily due to an overconsumption of food coupled with a reduction in physical activity. A natural antidote to both obesity and type 2 diabetes is to choose a healthy lifestyle, including a low-calorie diet and increased physical activity. However, many do not choose this option, and for some advanced patients, increased physical activity is not possible. The response to overfeeding in humans is diverse: some store the excess calories almost entirely, whereas others metabolize most of them (3). The variation is strongly dependent on both lifestyle and genetics. As strenuous activity was limited in some of these protocols, the diversity of weight gain was attributed to light activities, such as fidgeting (3, 4). Alternatively, the diversity may be due to variation in the metabolic rate of resting muscle and to how this responds to activity (5).A pharmacological approach to combating obesity has been of limited value, of the order of 5-10% weight loss when combined with lifestyle changes (for review, see refs. 6 and 7). Therapies for type 2 diabetes produce little effect, with the exception of metformin (for review, see ref. 8). Lifestyle changes, including better diets and increased activity levels, have a larger effect than pharmaceuticals. Here we suggest a target for combating obesity and...

Imaging ATP Consumption in Resting Skeletal Muscle: One Molecule at a Time

“…2B; Table 1). These time constants are in remarkable agreement with fiber-level measurements in rabbit soleus muscle (5,12), suggesting that the longer lifetime population is reflective of SRX myosin in the myofibril preparation.…”

Omecamtiv mercabil and blebbistatin modulate cardiac contractility by perturbing the regulatory state of the myosin filament

“…To supplement the approach of looking for small molecules like OM and BS that perturb the actin‐myosin ATPase cycle as determined with soluble myosin fragments that do not form filaments, it might be possible to design or screen for molecules that perturb the regulatory state of the thick filament without large effects on the actin‐myosin ATPase (Nogara et al . ). In principle, and in contrast with OM, such molecules could be simple activators without competing inhibitory effects, which might facilitate the selection of a therapeutic dose.…”

Therapeutic Potential of Polyphenols in Cardiac Fibrosis

“…A previous study found that piperine could attenuate weight gain in rodents (BrahmaNaidu et al, 2014 ), and the beneficial effect of piperine was associated with the up-regulation of the metabolic rate of resting muscle (Nogara et al, 2016 ). In the metabolic syndrome model, piperine reduced ventricular wall thickness and attenuated cardiac collagen deposition in rats fed a high-fat diet (Diwan et al, 2013 ).…”