(1) Background: Capsaicin, a chief ingredient of natural chili peppers, enhances metabolism and energy expenditure and stimulates the browning of white adipose tissue (WAT) and brown fat activation to counter diet-induced obesity. Although capsaicin and its nonpungent analogs are shown to enhance energy expenditure, their efficiency to bind to and activate their receptor—transient receptor potential vanilloid subfamily 1 (TRPV1)—to mediate thermogenic effects remains unclear. (2) Methods: We analyzed the binding efficiency of capsaicin analogs by molecular docking. We fed wild type mice a normal chow or high fat diet (± 0.01% pungent or nonpungent capsaicin analog) and isolated inguinal WAT to analyze the expression of thermogenic genes and proteins. (3) Results: Capsaicin, but not its nonpungent analogs, efficiently binds to TRPV1, prevents high fat diet-induced weight gain, and upregulates thermogenic protein expression in WAT. Molecular docking studies indicate that capsaicin exhibits the highest binding efficacy to TRPV1 because it has a hydrogen bond that anchors it to TRPV1. Capsiate, which lacks the hydrogen bond, and therefore, does not anchor to TRPV1. (4) Conclusions: Long-term activation of TRPV1 is imminent for the anti-obesity effect of capsaicin. Efforts to decrease the pungency of capsaicin will help in advancing it to mitigate obesity and metabolic dysfunction in humans.

Capsaicin (CAP) activates transient receptor potential vanilloid subfamily 1 (TRPV1) to counter high-fat diet (HFD)-induced obesity. Several studies suggest that CAP induces the browning of white adipocytes in vitro or inguinal white adipose tissue (iWAT) in vivo . However, there is a lack of data on the dose-response for CAP to inhibit HFD-induced obesity. Therefore, we first performed experiments to correlate the effect of various doses of CAP to prevent HFD-induced weight gain in wild-type (WT) mice. Next, we performed a subchronic safety study in WT mice fed a normal chow diet (NCD ± CAP, 0.01% in NCD) or HFD ± CAP (0.01% in HFD) for eight months. We analyzed the expression of adipogenic and thermogenic genes and proteins in the iWAT from these mice, conducted histological studies of vital organs, measured the inflammatory cytokines in plasma and iWAT, and evaluated liver and kidney functions. The dose-response study showed that CAP, at doses above 0.001% in HFD, countered HFD-induced obesity in mice. However, no difference in the anti-obesity effect of CAP was observed at doses above 0.003% in HFD. Also, CAP, above 0.001%, enhanced the expression of sirtuin-1 and thermogenic uncoupling protein 1 (UCP-1) in the iWAT. Safety analyses suggest that CAP did not cause inflammation. However, HFD elevated plasma alanine aminotransferase and creatinine, caused iWAT hypertrophy and hepatic steatosis, and CAP reversed these. Our data suggest that CAP antagonizes HFD-induced metabolic stress and inflammation, while it does not cause any systemic toxicities and is well tolerated by mice.

Supplemental Digital Content is Available in the Text.A highly penetrable nanoparticle cream formulation of resiniferatoxin has been developed and demonstrated its effectiveness in small and large animal models of painful diabetic peripheral neuropathy.

Metabocin TM (also known as capsaicin) activates TRPV1 expressed on the membranes of white adipocytes to cause browning of white adipocytes. Although, our sub-chronic Metabocin TM -feeding neither altered the energy intake nor any adverse reactions in mice, it is essential to demonstrate the safety of MetabocinTM in preclinical toxicological studies in mice. Keeping this goal in mind, we conducted a dose response for Metabocin TM (0.133, 0.399, 0.665, 1.33 or 3.99 mg/kg body weight of mouse corresponding to 0.001, 0.003, 0.005, 0.01 and 0.03% of Metabocin TM in diet) to counter obesity in high fat diet-fed wild type mice. We conducted histopathological studies and analyzed the plasma levels of markers metabolic, liver and kidney functions. To ensure that Metabocin TM does not cause adverse reactions when in normal chow diet (NCD), we fed wild type mice a diet containing 0.01% MetabocinTM in NCD. Our data show that MetabocinTM inhibited diet-induced obesity at concentration above 0.001% (0.133 mg/kg body weight) and the theoretical EC50 of Metabocin TM is determined to 0.00157% (0.2881 mg/kg body weight). Metabocin TM did not alter food/water intake in mice in any of the concentrations used. HFD feeding increased fasting plasma glucose, triglycerides and cholesterol levels and significantly elevated serum alanine aminotransferase and creatinine levels, and Metabocin TM antagonized this. Metabocin TM countered hypertension associated with obesity at all concentrations except 0.003%.