title: 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 high-throughput 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 Kdwas ∼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.
authors: Dipartimento di Scienze Biomediche, University of Padua, Padua, Italy 35122.
authors: Leonardo
authors: 0000-0002-7009-8707
authors: L
authors: Nogara
authors: Department of Biochemistry, University of California, San Francisco, CA 94158.
authors: Nariman
authors: N
authors: Naber
authors: Voiland School of Bioengineering, Washington State University, Pullman, WA 99163.
authors: Edward
authors: E
authors: Pate
authors: Dipartimento di Scienze Biomediche, University of Padua, Padua, Italy 35122.
authors: Marcella
authors: M
authors: Canton
authors: Dipartimento di Scienze Biomediche, University of Padua, Padua, Italy 35122.
authors: Carlo
authors: C
authors: Reggiani
authors: Department of Biochemistry, University of California, San Francisco, CA 94158; cooke@cgl.ucsf.edu.
authors: Roger
authors: R
authors: Cooke
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001481:Basal Metabolism / Q000187:drug effects*; D052117:Benzodioxoles / Q000494:pharmacology* / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D057166:High-Throughput Screening Assays; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects* / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D053284:Polyunsaturated Alkamides / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D024744:Skeletal Muscle Myosins / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000470:Alkaloids; D052117:Benzodioxoles; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D000251:Adenosine Triphosphatases; D024744:Skeletal Muscle Myosins; C008922:piperine
keywords: fluorescence; myosin; obesity; skeletal muscle; super-relaxed state