Prolonged Treatment with Grains of Paradise (Aframomum melegueta) Extract Recruits Adaptive Thermogenesis and Reduces Body Fat in Humans with Low Brown Fat Activity.

Increasing adaptive thermogenesis through the activation of brown adipose tissue (BAT) is a promising practical strategy for preventing obesity and related disorders. Ingestion of a single dose of 40 mg of an extract of Grains of Paradise (GP), a ginger family species, reportedly triggers BAT thermogenesis in individuals with high but not in those with low BAT activity. We hypothesized that prolonged treatment with GP might revive BAT in individuals who have lost active BAT. In the present study, we recruited 9 healthy young male volunteers with reduced BAT that was assessed by fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT) following 2-h cold exposure at 19ºC. The subjects ingested GP extract (40 mg/d) or placebo every day for 5 wk. Before and after the treatment with either GP or placebo, their body composition and BAT-dependent cold-induced thermogenesis (CIT)-a non-invasive index of BAT-were measured in a single-blinded, randomized, placebo-controlled cross-over design. Their whole-body resting energy expenditure at a thermoneutral condition remained unchanged following GP treatment. However, CIT after treatment was significantly higher in GP-treated individuals than in placebo-treated individuals. Body weight and fat-free mass did not change significantly following GP or placebo treatment. Notably, body fat percentage slightly but significantly decreased after GP treatment but not after placebo treatment. These results suggest that repeated ingestion of GP elevates adaptive thermogenesis through the re-activation of BAT, thereby reducing body fat in individuals with low BAT activity.

Tea catechin and caffeine activate brown adipose tissue and increase cold-induced thermogenic capacity in humans.

Background: The thermogenic effects of green tea catechin have been repeatedly reported, but their mechanisms are poorly understood.Objective: The aim of this study was to investigate the acute and chronic effects of catechin on brown adipose tissue (BAT), a site specialized for nonshivering thermogenesis, in humans.Design: Fifteen healthy male volunteers underwent fluorodeoxyglucose-positron emission tomography to assess BAT activity. To examine the acute catechin effect, whole-body energy expenditure (EE) after a single oral ingestion of a beverage containing 615 mg catechin and 77 mg caffeine (catechin beverage) was measured. Next, to investigate the chronic catechin effects, 10 men with low BAT activity were enrolled. Before and after ingestion of the catechin beverage 2 times/d for 5 wk, cold-induced thermogenesis (CIT) after 2 h of cold exposure at 19°C, which is proportional to BAT activity, was examined. Both the acute and chronic trials were single-blinded, randomized, placebo-controlled, season-matched crossover studies.Results: A single ingestion of the catechin beverage increased EE in 9 subjects who had metabolically active BAT (mean ± SEM: +15.24 ± 1.48 kcal, P < 0.01) but not in 6 subjects who had negligible activities (mean ± SEM: +3.42 ± 2.68 kcal). The ingestion of a placebo beverage containing 82 mg caffeine produced a smaller and comparative EE response in the 2 subject groups. Multivariate regression analysis revealed a significant interaction between BAT and catechin on EE (ß = 0.496, P = 0.003). Daily ingestion of the catechin beverage elevated mean ± SEM CIT (from 92.0 ± 26.5 to 197.9 ± 27.7 kcal/d; P = 0.009), whereas the placebo beverage did not change it.Conclusion: Orally ingested tea catechin with caffeine acutely increases EE associated with increased BAT activity and chronically elevates nonshivering CIT, probably because of the recruitment of BAT, in humans. These trials were registered at www.umin.ac.jp/ctr/ as UMIN000016361.

Capsaicin and Related Food Ingredients Reducing Body Fat Through the Activation of TRP and Brown Fat Thermogenesis.

Brown adipose tissue (BAT) is a site of sympathetically activated adaptive nonshivering thermogenesis, thereby being involved in the regulation of energy balance and body fatness. Recent radionuclide imaging studies have revealed the existence of metabolically active BAT in adult humans. Human BAT is activated by acute cold exposure and contributes to cold-induced increase in whole-body energy expenditure. The metabolic activity of BAT is lower in older and obese individuals. The inverse relationship between the BAT activity and body fatness suggests that BAT, because of its energy dissipating activity, is protective against body fat accumulation. In fact, repeated cold exposure recruits BAT in association with increased energy expenditure and decreased body fatness. The stimulatory effects of cold are mediated through the activation of transient receptor potential (TRP) channels, most of which are also chemesthetic receptors for various naturally occurring substances including herbal plants and food ingredients. Capsaicin and its analog capsinoids, representative agonists of TRPV1, mimic the effects of cold to decrease body fatness through the activation and recruitment of BAT. The well-known antiobesity effect of green tea catechins is also attributable to the activation of the sympathetic nerve and BAT system. Thus, BAT is a promising target for combating obesity and related metabolic disorders in humans.

Kaempferia parviflora extract increases whole-body energy expenditure in humans: roles of brown adipose tissue.

Kaempferia parviflora extract (KP) has been reported to have a preventive effect on obesity in mice, probably by increasing energy expenditure (EE). The aims of the current study were to examine the acute effects of KP ingestion on whole-body EE in humans and to analyze its relation to the activity of brown adipose tissue (BAT), a site of non-shivering thermogenesis. After an oral ingestion of an ethanol extract of KP, EE increased significantly, showing a maximal increase of 229±69 kJ/d at 60 min, while it did not change after placebo ingestion. To evaluate BAT activity, the subjects underwent fluorodeoxyglucose-positron emission tomography, and divided into two groups with high- and low-BAT activities. A similar and greater response of EE to KP ingestion was observed in the high-BAT group (351±50 kJ/d at 60 min), but not in the low activity group. Placebo ingestion did not cause any significant EE change in either group. These results indicate that a single oral ingestion of the KP extract can potentially increase whole-body EE probably through the activation of BAT in healthy men, and may be useful as an anti-obesity regimen.

Daily ingestion of grains of paradise (Aframomum melegueta) extract increases whole-body energy expenditure and decreases visceral fat in humans.

We reported previously that a single ingestion of an alcohol extract of grains of paradise (GP, Aframomum melegueta), a species of the ginger family, increases energy expenditure (EE) through the activation of brown adipose tissue, a site of sympathetically mediated metabolic theromogenesis. The present study aimed to examine a daily ingestion of GP extract on whole-body EE and body fat in humans. Whole-body EE and body fat content were measured before and after daily oral ingestion of GP extract (30 mg/d) for 4 wk in 19 non-obese female volunteers aged 20-22 y in a single-blind, randomized, placebo-controlled, crossover design. Four-week daily ingestion of GP and a placebo decreased and increased slightly the visceral fat area at the umbilicus level, respectively. The GP-induced change was significantly different from that induced by the placebo (p<0.05), and negatively correlated with the initial visceral fat area (r=-0.64, p<0.01). Neither GP nor placebo ingestion affected subcutaneous or total fat. The daily ingestion of GP, but not the placebo, increased whole-body EE (p<0.05). These results suggest that GP extract may be an effective and safe tool for reducing body fat, mainly by preventing visceral fat accumulation.

Transient receptor potential activated brown fat thermogenesis as a target of food ingredients for obesity management.

PURPOSE OF REVIEW: Cold exposure activates brown adipose tissue (BAT), the major site of sympathetically activated nonshivering thermognenesis, via transient receptor potential (TRP) channels. Capsaicin and its nonpungent analogue (capsinoids) are agonists for a vanilloid subtype one of TRP, and have the potential to increase whole-body energy expenditure and reduce body fat. This article reviews the regulatory roles of BAT for energy expenditure and body fat in humans, particularly focusing on food ingredients activating the TRP-BAT axis. RECENT FINDINGS: Acute cold exposure increased energy expenditure in humans with metabolically active BAT, but not those without it. Quite similar responses were found after a single oral ingestion of either capsinoids or an alcohol extract of Guinea pepper seeds, indicating that these food ingredients activate BAT and thereby increase energy expenditure. When individuals without active BAT were exposed to cold every day for 6 weeks, BAT was recruited in association with increased energy expenditure and decreased body fat. A 6-week daily ingestion of capsinoids mimicked the effects of repeated cold exposure. These findings indicate that human BAT can be reactivated/recruited, thereby increasing energy expenditure and decreasing body fat. SUMMARY: Human BAT recruited by prolonged ingestion of a vanilloid subtype one of TRP agonists increases energy expenditure and decreases body fat. In addition to capsinoids, there are numerous food ingredients acting as TRP agonists, which are expected to activate BAT and so be useful for the prevention of obesity in daily life.

Miglitol prevents diet-induced obesity by stimulating brown adipose tissue and energy expenditure independent of preventing the digestion of carbohydrates.

Miglitol is an alpha-glucosidase inhibitor that improves post-prandial hyperglycemia, and it is the only drug in its class that enters the bloodstream. Anecdotally, miglitol lowers patient body weight more effectively than other alpha-glucosidase inhibitors, but the precise mechanism has not been addressed. Therefore, we analyzed the anti-obesity effects of miglitol in mice and in the HB2 brown adipocyte cell line. Miglitol prevented diet-induced obesity by stimulating energy expenditure without affecting food intake in mice. Long-term miglitol treatment dose-dependently prevented diet-induced obesity and induced mitochondrial gene expression in brown adipose tissue. The anti-obesity effect was independent of preventing carbohydrate digestion in the gastrointestinal tract. Miglitol effectively stimulated energy expenditure in mice fed a high-fat high-monocarbohydrate diet, and intraperitoneal injection of miglitol was sufficient to stimulate energy expenditure in mice. Acarbose, which is a non-absorbable alpha glucosidase inhibitor, also prevented diet-induced obesity, but through a different mechanism: it did not stimulate energy expenditure, but caused indigestion, leading to less energy absorption. Miglitol promoted adrenergic signaling in brown adipocytes in vitro. These data indicate that circulating miglitol stimulates brown adipose tissue and increases energy expenditure, thereby preventing diet-induced obesity. Further optimizing miglitol's effect on brown adipose tissue could lead to a novel anti-obesity drug.

Recruited brown adipose tissue as an antiobesity agent in humans.

Brown adipose tissue (BAT) burns fat to produce heat when the body is exposed to cold and plays a role in energy metabolism. Using fluorodeoxyglucose-positron emission tomography and computed tomography, we previously reported that BAT decreases with age and thereby accelerates age-related accumulation of body fat in humans. Thus, the recruitment of BAT may be effective for body fat reduction. In this study, we examined the effects of repeated stimulation by cold and capsinoids (nonpungent capsaicin analogs) in healthy human subjects with low BAT activity. Acute cold exposure at 19°C for 2 hours increased energy expenditure (EE). Cold-induced increments of EE (CIT) strongly correlated with BAT activity independently of age and fat-free mass. Daily 2-hour cold exposure at 17°C for 6 weeks resulted in a parallel increase in BAT activity and CIT and a concomitant decrease in body fat mass. Changes in BAT activity and body fat mass were negatively correlated. Similarly, daily ingestion of capsinoids for 6 weeks increased CIT. These results demonstrate that human BAT can be recruited even in individuals with decreased BAT activity, thereby contributing to body fat reduction.

Grains of paradise (Aframomum melegueta) extract activates brown adipose tissue and increases whole-body energy expenditure in men.

Brown adipose tissue (BAT) is responsible for cold- and diet-induced thermogenesis, and thereby contributes to the control of whole-body energy expenditure (EE) and body fat content. BAT activity can be assessed by fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET) in human subjects. Grains of paradise (GP, Aframomum melegueta), a species of the ginger family, contain pungent, aromatic ketones such as 6-paradol, 6-gingerol and 6-shogaol. An alcohol extract of GP seeds and 6-paradol are known to activate BAT thermogenesis in small rodents. The present study aimed to examine the effects of the GP extract on whole-body EE and to analyse its relation to BAT activity in men. A total of nineteen healthy male volunteers aged 20-32 years underwent FDG-PET after 2 h of exposure to cold at 19°C with light clothing. A total of twelve subjects showed marked FDG uptake into the adipose tissue of the supraclavicular and paraspinal regions (BAT positive). The remaining seven showed no detectable uptake (BAT negative). Within 4 weeks after the FDG-PET examination, whole-body EE was measured at 27°C before and after oral ingestion of GP extract (40 mg) in a single-blind, randomised, placebo-controlled, crossover design. The resting EE of the BAT-positive group did not differ from that of the BAT-negative group. After GP extract ingestion, the EE of the BAT-positive group increased within 2 h to a significantly greater (P<0·01) level than that of the BAT-negative group. Placebo ingestion produced no significant change in EE. These results suggest that oral ingestion of GP extract increases whole-body EE through the activation of BAT in human subjects.

Capsinoids and related food ingredients activating brown fat thermogenesis and reducing body fat in humans.

PURPOSE OF REVIEW: Capsaicin and its nonpungent analog (capsinoids) are known to be food ingredients that increase energy expenditure and decrease body fat. This article reviews the role of brown adipose tissue (BAT) for the thermogenic effect of these compounds in humans and proposes the possibility of some other antiobesity food ingredients. RECENT FINDINGS: A single oral ingestion of capsinoids increases energy expenditure in human individuals with metabolically active BAT, but not those without it, indicating that capsinoids activate BAT and thereby increase energy expenditure. This finding gave a rational explanation for discrepant results of the effects of capsinoids in the previous studies. Human BAT may be largely composed of inducible 'beige' adipocytes more than typical brown adipocytes because its gene expression patterns are similar to beige cells isolated from murine white fat depots. In fact, preadipocytes isolated from supraclavicular fat deposits - where BAT is often detected - are capable of differentiating into brown-like adipocytes in vitro, providing evidence of inducible brown adipogenesis in adult humans. SUMMARY: As human BAT may be inducible, a prolonged ingestion of capsinoids would recruit active BAT and thereby increase energy expenditure and decrease body fat. In addition to capsinoids, there are numerous food ingredients that are expected to activate BAT and so be useful for the prevention of obesity in daily life.

Brown adipose tissue as a therapeutic target for human obesity.

Brown adipose tissue (BAT) is the major site of sympathetically activated adaptive thermogenesis during cold exposure and after spontaneous hyperphagia, thereby controlling whole-body energy expenditure and body fat. Recent radionuclide studies have demonstrated the existence of metabolically active BAT in healthy adult humans. Human BAT is activated by acute cold exposure, being positively correlated to cold-induced increases in energy expenditure. The metabolic activity of BAT is lower in older and obese individuals. The inverse relationship between the BAT activity and body fatness suggests that BAT, because of its energy dissipating activity, is protective against body fat accumulation. In fact, either repeated cold exposure or daily ingestion of some food ingredients acting on transient receptor potential channels recruited BAT in association with increased energy expenditure and decreased body fat even in individuals with low BAT activities before the treatment. Thus, BAT is a promising therapeutic target for combating human obesity and related metabolic disorders.

Nonpungent capsaicin analogs (capsinoids) increase energy expenditure through the activation of brown adipose tissue in humans.

BACKGROUND: Capsinoids-nonpungent capsaicin analogs-are known to activate brown adipose tissue (BAT) thermogenesis and whole-body energy expenditure (EE) in small rodents. BAT activity can be assessed by [¹8F]fluorodeoxyglucose-positron emission tomography (FDG-PET) in humans. OBJECTIVES: The aims of the current study were to examine the acute effects of capsinoid ingestion on EE and to analyze its relation to BAT activity in humans. DESIGN: Eighteen healthy men aged 20-32 y underwent FDG-PET after 2 h of cold exposure (19°C) while wearing light clothing. Whole-body EE and skin temperature, after oral ingestion of capsinoids (9 mg), were measured for 2 h under warm conditions (27°C) in a single-blind, randomized, placebo-controlled, crossover design. RESULTS: When exposed to cold, 10 subjects showed marked FDG uptake into adipose tissue of the supraclavicular and paraspinal regions (BAT-positive group), whereas the remaining 8 subjects (BAT-negative group) showed no detectable uptake. Under warm conditions (27°C), the mean (±SEM) resting EE was 6114 ± 226 kJ/d in the BAT-positive group and 6307 ± 156 kJ/d in the BAT-negative group (NS). EE increased by 15.2 ± 2.6 kJ/h in 1 h in the BAT-positive group and by 1.7 ± 3.8 kJ/h in the BAT-negative group after oral ingestion of capsinoids (P < 0.01). Placebo ingestion produced no significant change in either group. Neither capsinoids nor placebo changed the skin temperature in various regions, including regions close to BAT deposits. CONCLUSION: Capsinoid ingestion increases EE through the activation of BAT in humans. This trial was registered at http://www.umin.ac.jp/ctr/ as UMIN 000006073.

Possible involvement of uncoupling protein 1 in appetite control by leptin.

Leptin reduces body fat by decreasing food intake and increasing energy expenditure. Uncoupling protein (UCP) 1, a key molecule for brown adipose tissue (BAT) thermogenesis, was reported to contribute to the stimulatory effect of leptin on energy expenditure. To clarify whether UCP1 is also involved in the anorexigenic effect of leptin, in this study we examined the effect of leptin on food intake using wild-type (WT) and UCP1-deficient (UCP1-KO) mice. Repeated injection of leptin decreased food intake more markedly in WT mice than in UCP1-KO mice, while a single injection of leptin showed similar effects in the two groups of mice. As chronic leptin stimulation induces UCP1 expression in BAT and ectopically in white adipose tissue (WAT), we mimicked the UCP1 induction by repeated injection of CL316,243 (CL), a highly specific ß3-adrenoceptor agonist, and measured food intake in response to a single injection of leptin. Two-week treatment with CL enhanced the anorexigenic effect of leptin in WT mice, but not in UCP1-KO mice. Three-day treatment with CL in WT mice also enhanced the anorexigenic effect of leptin and leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) in the arcuate nucleus of the hypothalamus, without any notable change in adiposity. These results indicate that UCP1 enhances leptin action at the hypothalamus level, suggesting UCP1 contributes to the control of energy balance not only through the regulation of energy expenditure but also through appetite control by modulating leptin action.

Enhancement of lipolytic responsiveness of adipocytes by novel plant extract in rat.

Subcutaneous adipocytes accumulate excess energy as triglycerides, but lipolytic response is less sensitive to catecholamines than visceral adipocytes. Obesity also induces catecholamine resistance of adipocytes. We have searched for crude drugs that could enhance the lipolytic response to noradrenalin. In this study, the lipolysis-promoting activities and action mechanisms of a novel plant extract from Hemerocallis fulva (HE) were investigated in isolated adipocytes from rat subcutaneous fat. HE exhibited no lipolysis-promoting activity alone but markedly promoted lipolysis when combined with noradrenaline; however, this synergistic activity was accompanied by no increase of intracellular cAMP production. This activity of HE was also observed when combined with cAMP analogue and was further enhanced by phosphodiesterase inhibitor. PKA inhibitor could reduce these activities of HE. These results indicate that HE is a novel lipolysis-promoting material that can sensitize the lipolytic response of adipocytes to catecholamine and suggest that HE can amplify the intra-cellular signaling pathway related to PKA or modify the other mechanism-regulating lipase activity. This characteristic material could contribute to improvement of adipose mobility in obesity-related disorder or in subcutaneous adiposity and to suppression of body fat accumulation.

Dmbx1 is essential in agouti-related protein action.

Dmbx1 is a paired-class homeodomain transcription factor. We show here that mice deficient in Dmbx1 exhibit severe leanness associated with hypophagia and hyperactivity and that isolation of a Dmbx1(-/-) mouse from its cohabitants induces self-starvation, sometimes leading to death, features similar to those of anorexia nervosa in humans. Interestingly, overexpression of agouti in Dmbx1(-/-) mice failed to induce aspects of the A(y)/a phenotype, including hyperphagia, obesity, and diabetes mellitus. In Dmbx1(-/-) mice, administration of agouti-related protein increased cumulative food intake for the initial 6 h but significantly decreased it over 24- and 48-h periods. In addition, Dmbx1 was shown to be expressed at embryonic day 15.5 in the lateral parabrachial nucleus, the rostral nucleus of the tractus solitarius, the dorsal motor nucleus of the vagus, and the reticular nucleus in the brainstem, all of which receive melanocortin signaling, indicating involvement of Dmbx1 in the development of the neural network for the signaling. Thus, Dmbx1 is essential for various actions of agouti-related protein and plays a role in normal regulation of energy homeostasis and behavior.

Conjugated linoleic acid deteriorates insulin resistance in obese/diabetic mice in association with decreased production of adiponectin and leptin.

Dietary supplementation of conjugated linoleic acids (CLA) is known to have some beneficial effects such as anti-carcinogenic and anti-obesity effects in several animal species, while it also induces insulin resistance and fatty liver, especially in mice. To explore the possible factors responsible for the CLA-induced insulin resistance, we examined the plasma and mRNA expression levels of several adipocytokines, which are likely involved in the regulation of insulin sensitivity, in normal C5 7BL, mildly obese/diabetic KK and morbidly obese/diabetic KKAy mice. Feeding a diet supplemented with 0.5%, CLA oil consisting of 30.5/% c9, t11-CLA and 28.9% t10, c12-CLA for 4 wk resulted in a decrease in white adipose tissue (WAT), an increase in liver weight with excess accumulation of triglyceride, and insulin resistance associated with hyperglycemia and hyperinsulinemia. The plasma and WAT mRNA levels of leptin were higher in KK and KKAy mice than C57BI. mice, whereas those of adiponectin were higher in C5 7BL mice. CLA-feeding decreased the levels of leptin, adiponectin and resistin, especially in KK and KKAy mice. In contrast, tumor necrosis factor-alpha (TNFalpha) mRNA levels were higher in KK and KKAy mice than C57BL mice, and were increased by CLA feeding. The present results thus indicate that CLA feeding promotes insulin resistance in obese/diabetic mice by at least inverse regulation of leptin and adiponectin, and TNFalpha, adipocytokines known to either ameliorate or deteriorate insulin sensitivity, respectively.

Dual action of isoprenols from herbal medicines on both PPARgamma and PPARalpha in 3T3-L1 adipocytes and HepG2 hepatocytes.

Several herbal medicines improve hyperlipidemia, diabetes and cardiovascular diseases. However, the molecular mechanism underlying this improvement has not yet been clarified. In this study, we found that several isoprenols, common components of herbal plants, activate human peroxisome proliferator-activated receptors (PPARs) as determined using the novel GAL4 ligand-binding domain chimera assay system with coactivator coexpression. Farnesol and geranylgeraniol that are typical isoprenols in herbs and fruits activated not only PPARgamma but also PPARalpha as determined using the chimera assay system. These compounds also activated full-length human PPARgamma and PPARalpha in CV1 cells. Moreover, these isoprenols upregulated the expression of some lipid metabolic target genes of PPARgamma and PPARalpha in 3T3-L1 adipocytes and HepG2 hepatocytes, respectively. These results suggest that herbal medicines containing isoprenols with dual action on both PPARgamma and PPARalpha can be of interest for the amelioration of lipid metabolic disorders associated with diabetes.