Combination of TRP channel dietary agonists induces energy expending and glucose utilizing phenotype in HFD-fed mice

Kaur, Jasleen; Kumar, Vijay; Kumar, Vikas; Shafi, Sadiah; Khare, Pragyanshu; Mahajan, Neha; Bhadada, Sanjay Kumar; Kondepudi, Kanthi Kiran; Bhunia, Rupam Kumar; Kuhad, Anurag; Bishnoi, Mahendra

doi:10.1038/s41366-021-00967-3

Cited by 12 publications

(17 citation statements)

References 67 publications

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“…Accumulating evidence 31,32,48,49,73 supports a role for pharmacologically targeting TRPM8 with MNTH to mimic the thermogenic effects of ambient cold exposure, and our data clearly expand on this literature by establishing the mechanism through which topical MNTH application works in a translationally relevant preclinical model of human metabolism. To date, only one other study has reported topically treating mice housed at a near thermoneutral temperature with MNTH, but unlike our current work at thermoneutrality, this study only made acute thermogenic measures under chow‐fed conditions and interestingly they anesthetized mice with isoflurane, a known inhibitor of BAT thermogenesis, 74,75 prior to each topical MNTH application 54 .…”

Section: Discussionsupporting

confidence: 68%

“…Accumulating evidence 31,32,48,49,73 supports a role for pharmacologically targeting TRPM8 with MNTH to mimic the thermogenic effects of ambient cold exposure, and reported topically treating mice housed at a near thermoneutral temperature with MNTH, but unlike our current work at thermoneutrality, this study only made acute thermogenic measures under chow-fed conditions and interestingly they anesthetized mice with isoflurane, a known inhibitor of BAT thermogenesis, 74,75 prior to each topical MNTH application. 54 More recently, two studies have demonstrated that a high-fat diet supplemented with MNTH (0.5%-1%) reduced body weight gain over 12-28 weeks in male mice, 31,50 and while this dietary MNTH-induced attenuation of weight gain was TRPM8dependent 31 and associated with increases in UCP1dependent thermogenesis, 31,50 both studies housed mice at sub-thermoneutral temperatures confounding measures of thermogenesis.…”

Section: Discussionmentioning

confidence: 79%

“…While our data is the first short-term study in mice housed at thermoneutrality to demonstrate the efficacy of topical MNTH application for weight management, humans express TRPM8 not only in peripheral sensory nerves, [51][52][53] but also in the liver, colon, and prostate. 76 Furthermore, agonizing TRPM8 within these tissues produces desirable physiological outcomes in multiple models of disease, including the dose-dependent reduction of cellular viability in human malignant melanoma cells, 77 improved hepatic steatosis scores in models of high-fat diet-induced obesity, 30,73 reduced inflammation in multiple models of ulcerative colitis, 78 and suppressed cellular migration in human prostate cancer cells. 79,80 Perhaps most importantly, topical application of MNTH to humans is associated with vasodilation and increased vascular conductance, 81 which is in contrast to other sympathomimetics such as the FDA-approved drug mirabegron that induces BAT thermogenesis but also produces unwanted cardiovascular effects.…”

Section: Discussionmentioning

confidence: 99%

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Topical application of the pharmacological cold mimetic menthol stimulates brown adipose tissue thermogenesis through a TRPM8, UCP1, and norepinephrine dependent mechanism in mice housed at thermoneutrality

et al. 2022

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Increasing whole-body energy expenditure via the pharmacological activation of uncoupling protein 1 (UCP1)-dependent brown adipose tissue (BAT) thermogenesis is a promising weight management strategy, yet most therapeutics studied in rodents to date either induce compensatory increases in energy intake, have thermogenic effects that are confounded by sub-thermoneutral housing temperatures or are not well tolerated in humans. Here, we sought to determine whether the non-invasive topical application of the pharmacological cold mimetic and transient receptor potential (TRP) cation channel subfamily M member 8 (TRPM8) agonist L-menthol (MNTH), could be used to stimulate BAT thermogenesis and attenuate weight gain in mice housed at thermoneutrality. Using three different strains of mice and multiple complimentary approaches to quantify thermogenesis in vivo, coupled with ex vivo models to quantify direct thermogenic effects, we were able to convincingly demonstrate the following: (1) acute topical MNTH application induces BAT thermogenesis in a TRPM8-and UCP1-dependent manner; (2) MNTH-induced BAT thermogenesis is sufficient to attenuate weight gain over time without affecting energy intake in lean and obese mice; (3) the ability of topical MNTH application to stimulate BAT thermogenesis is mediated, in part, by a central mechanism involving the release of norepinephrine. These data collectively suggest that topical application of MNTH may be a promising weight management strategy.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Topical application of the pharmacological cold mimetic menthol stimulates brown adipose tissue thermogenesis through a TRPM8, UCP1, and norepinephrine dependent mechanism in mice housed at thermoneutrality

et al. 2022

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“…In C57BL/6J mice, capsaicin (0.4 mg/kg) that was fed in combination with menthol (20 mg/kg) and cinnamaldehyde (2 mg/kg) also prevented HFD-induced weight gain [ 21 ]. This dietary protocol is known as the “triagonist regimen” since capsaicin is the archetypal agonist of TRPV1 [ 22 ], menthol activates TRPM8 [ 23 , 24 ], and cinnamaldehyde acts via TRPA1 [ 25 ].…”

Section: Dietary Capsaicin In Animal Experimentsmentioning

confidence: 99%

Capsaicin for Weight Control: “Exercise in a Pill” (or Just Another Fad)?

Szállaśi

2022

Pharmaceuticals

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Medical management of obesity represents a large unmet clinical need. Animal experiments suggest a therapeutic potential for dietary capsaicin, the pungent ingredient in hot chili peppers, to lose weight. This is an attractive theory since capsaicin has been a culinary staple for thousands of years and is generally deemed safe when consumed in hedonically acceptable, restaurant-like doses. This review critically evaluates the available experimental and clinical evidence for and against capsaicin as a weight control agent and comes to the conclusion that capsaicin is not a magic “exercise in a pill”, although there is emerging evidence that it may help restore a healthy gut microbiota.

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“…The effects of capsaicin, the major pungent component of chili peppers, and its analogs capsinoids on BAT-mediated thermogenesis and EE have been intensively studied. On the other hand, previous studies have demonstrated that chemical activation of TRP channels by food ingredients can recruit and activate BAT in humans and animal models [ 111 , 112 , 113 ]. The transient receptor potential vanilloid (TRPV)1 located on primary afferent neurons has been speculated to be a primary target for capsinoids [ 114 ].…”

Section: Food-derived Stimulants and Diet-induced Bat Thermogenesismentioning

confidence: 99%

The Role and Regulatory Mechanism of Brown Adipose Tissue Activation in Diet-Induced Thermogenesis in Health and Diseases

Chan

Hsieh

2022

IJMS

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Brown adipose tissue (BAT) has been considered a vital organ in response to non-shivering adaptive thermogenesis, which could be activated during cold exposure through the sympathetic nervous system (SNS) or under postprandial conditions contributing to diet-induced thermogenesis (DIT). Humans prefer to live within their thermal comfort or neutral zone with minimal energy expenditure created by wearing clothing, making shelters, or using an air conditioner to regulate their ambient temperature; thereby, DIT would become an important mechanism to counter-regulate energy intake and lipid accumulation. In addition, there has been a long interest in the intriguing possibility that a defect in DIT predisposes one to obesity and other metabolic diseases. Due to the recent advances in methodology to evaluate the functional activity of BAT and DIT, this updated review will focus on the role and regulatory mechanism of BAT biology in DIT in health and diseases and whether these mechanisms are applicable to humans.

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Combination of TRP channel dietary agonists induces energy expending and glucose utilizing phenotype in HFD-fed mice

Cited by 12 publications

References 67 publications

Topical application of the pharmacological cold mimetic menthol stimulates brown adipose tissue thermogenesis through a TRPM8, UCP1, and norepinephrine dependent mechanism in mice housed at thermoneutrality

Topical application of the pharmacological cold mimetic menthol stimulates brown adipose tissue thermogenesis through a TRPM8, UCP1, and norepinephrine dependent mechanism in mice housed at thermoneutrality

Capsaicin for Weight Control: “Exercise in a Pill” (or Just Another Fad)?

The Role and Regulatory Mechanism of Brown Adipose Tissue Activation in Diet-Induced Thermogenesis in Health and Diseases

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