Yoshihito Nogusa

Intragastric administration of capsiate, a transient receptor potential channel agonist, triggers thermogenic sympathetic responses

The sympathetic thermoregulatory system controls the magnitude of adaptive thermogenesis in correspondence with the environmental temperature or the state of energy intake and plays a key role in determining the resultant energy storage. However, the nature of the trigger initiating this reflex arc remains to be determined. Here, using capsiate, a digestion-vulnerable capsaicin analog, we examined the involvement of specific activation of transient receptor potential (TRP) channels within the gastrointestinal tract in the thermogenic sympathetic system by measuring the efferent activity of the postganglionic sympathetic nerve innervating brown adipose tissue (BAT) in anesthetized rats. Intragastric administration of capsiate resulted in a time- and dose-dependent increase in integrated BAT sympathetic nerve activity (SNA) over 180 min, which was characterized by an emergence of sporadic high-activity phases composed of low-frequency bursts. This increase in BAT SNA was abolished by blockade of TRP channels as well as of sympathetic ganglionic transmission and was inhibited by ablation of the gastrointestinal vagus nerve. The activation of SNA was delimited to BAT and did not occur in the heart or pancreas. These results point to a neural pathway enabling the selective activation of the central network regulating the BAT SNA in response to a specific stimulation of gastrointestinal TRP channels and offer important implications for understanding the dietary-dependent regulation of energy metabolism and control of obesity.

A combination of exercise and capsinoid supplementation additively suppresses diet-induced obesity by increasing energy expenditure in mice.

Exercise effectively prevents the development of obesity and obesity-related diseases such as type 2 diabetes. Capsinoids (CSNs) are capsaicin analogs found in a nonpungent pepper that increase whole body energy expenditure. Although both exercise and CSNs have antiobesity functions, the effectiveness of exercise with CSN supplementation has not yet been investigated. Here, we examined whether the beneficial effects of exercise could be further enhanced by CSN supplementation in mice. Mice were randomly assigned to four groups: 1) high-fat diet (HFD, Control), 2) HFD containing 0.3% CSNs, 3) HFD with voluntary running wheel exercise (Exercise), and 4) HFD containing 0.3% CSNs with voluntary running wheel exercise (Exercise + CSN). After 8 wk of ingestion, blood and tissues were collected and analyzed. Although CSNs significantly suppressed body weight gain under the HFD, CSN supplementation with exercise additively decreased body weight gain and fat accumulation and increased whole body energy expenditure compared with exercise alone. Exercise together with CSN supplementation robustly improved metabolic profiles, including the plasma cholesterol level. Furthermore, this combination significantly prevented diet-induced liver steatosis and decreased the size of adipocyte cells in white adipose tissue. Exercise and CSNs significantly increased cAMP levels and PKA activity in brown adipose tissue (BAT), indicating an increase of lipolysis. Moreover, they significantly activated both the oxidative phosphorylation gene program and fatty acid oxidation in skeletal muscle. These results indicate that CSNs efficiently promote the antiobesity effect of exercise, in part by increasing energy expenditure via the activation of fat oxidation in skeletal muscle and lipolysis in BAT.

Catechin-Rich Grape Seed Extract Supplementation Attenuates Diet-Induced Obesity in C57BL/6J Mice

Background: Grape seed extracts (GSE) are known to present health benefits such as antioxidative and anti-obesity effects in animal models. The purpose of this research is to determine whether the specially manufactured GSE, catechin-rich GSE (CGSE), can protect against obesity induced by a high-fat diet (HFD) and to address the mechanism underlying this effect. Methods: The componential analysis of CGSE was performed using liquid chromatography/mass spectrometry. Oxygen consumption and the respiratory quotient were determined using 500 mg/kg CGSE administered orally for 3 days in 14- to 15-week-old male C57BL/6J mice. Nine-week-old male C57BL/6J mice were supplemented with 0.5 or 1% CGSE in a HFD for 12 weeks, and their body weight and food intake were monitored. Blood and tissue samples were collected and analyzed. Results: The main polyphenol components of CGSE were catechin and epicatechin. CGSE supplementation in the HFD-induced obesity model chronically suppressed the increase in body weight and the weight of fat pads. Furthermore, CGSE improved metabolic parameter abnormalities and upregulated the fatty acid oxidation-related genes in the liver. Conclusions: These findings suggest that CGSE contains monomeric catechins in high concentrations and ameliorates HFD-induced obesity in C57BL/6J mice.

A Synergistic Antiobesity Effect by a Combination of Capsinoids and Cold Temperature Through Promoting Beige Adipocyte Biogenesis.

Beige adipocytes emerge postnatally within the white adipose tissue in response to certain environmental cues, such as chronic cold exposure. Because of its highly recruitable nature and relevance to adult humans, beige adipocytes have gained much attention as an attractive cellular target for antiobesity therapy. However, molecular circuits that preferentially promote beige adipocyte biogenesis remain poorly understood. We report that a combination of mild cold exposure at 17°C and capsinoids, a nonpungent analog of capsaicin, synergistically and preferentially promotes beige adipocyte biogenesis and ameliorates diet-induced obesity. Gain- and loss-of-function studies show that the combination of capsinoids and cold exposure synergistically promotes beige adipocyte development through the β2-adrenoceptor signaling pathway. This synergistic effect on beige adipocyte biogenesis occurs through an increased half-life of PRDM16, a dominant transcriptional regulator of brown/beige adipocyte development. We document a previously unappreciated molecular circuit that controls beige adipocyte biogenesis and suggest a plausible approach to increase whole-body energy expenditure by combining dietary components and environmental cues.

Different TRPV1-mediated brain responses to intragastric infusion of capsaicin and capsiate.

Capsaicin and capsiate, which is an analogue of capsaicin, are agonists of capsaicin‐binding transient potential vanilloid 1 (TRPV1) receptors. However, their physiological effects are different. Capsaicin induces thermogenesis and nociception, while the different kinetics of capsiate result in thermogenesis without nociception in the oral cavity. In the present study, using functional magnetic resonance imaging, we compared the brain activation after intragastric infusion of non‐nociceptive levels of capsaicin and capsiate in wild‐type and TRPV1‐knockout (KO) mice. Capsaicin activated several brain regions, such as the periaqueductal grey (PAG), thalamic nuclei and hypothalamus, including the medial preoptic area (mPOA) and ventromedial hypothalamus (VMH). Most of these areas were not activated in TRPV1‐KO mice. Capsiate activated several regions, including the thalamic nuclei, mPOA and VMH but not PAG in wild‐type mice. Most of the activated areas were not activated by intragastric capsiate infusion in TRPV1‐KO mice. These results demonstrate that TRPV1 is critical for the induction of activation in the hypothalamus by capsaicin and capsiate, and these distinct brain activations could help to explain the individual physiological reactions of capsaicin and capsiate.