Brown Fat Activity Research Articles

Trans-Cinnamic Acid Stimulates White Fat Browning and Activates Brown Adipocytes.

Recently, pharmacological activation of brown fat and induction of white fat browning (beiging) have been considered promising strategies to treat obesity. To search for natural products that could stimulate the process of browning in adipocytes, we evaluated the activity of trans-cinnamic acid (tCA), a class of cinnamon from the bark of Cinnamomum cassia, by determining genetic expression using real time reverse transcription polymerase chain reaction (RT-PCR) and protein expression by immunoblot analysis for thermogenic and fat metabolizing markers. In our study tCA induced brown like-phenotype in 3T3-L1 white adipocytes and activated HIB1B brown adipocytes. tCA increased protein content of brown-fat-specific markers (UCP1, PRDM16, and PGC-1α) and expression levels of beige-fat-specific genes (Cd137, Cidea, Cited1, Tbx1, and Tmen26) in 3T3-L1 white adipocytes, as well as brown-fat-specific genes (Lhx8, Ppargc1, Prdm16, Ucp1, and Zic1) in HIB1B brown adipocytes. Furthermore, tCA reduced expression of key adipogenic transcription factors C/EBPα and PPARγ in white adipocytes, but enhanced their expressions in brown adipocytes. In addition, tCA upregulates lipid catabolism. Moreover, mechanistic study revealed that tCA induced browning in white adipocytes by activating the β3-AR and AMPK signaling pathways. tCA can induce browning, increase fat oxidation, reduce adipogenesis and lipogenesis in 3T3-L1 adipocytes, and activate HIB1B adipocytes, suggesting its potential to treat obesity.

MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction.

The postmenopausal state is associated with an increased risk of metabolic disorder including reduced energy expenditure and weight gain, leading to higher cardiovascular and cancer risks among other diseases. Mitochondrial-derived peptide (MOTS-c) is a 16-amino acid peptide encoded by mitochondrial DNA. Here, we showed that MOTS-c treatment in mice prevented ovariectomy-induced obesity and insulin resistance. After ovariectomy, low levels of estrogens increased fat mass overload and disturbed normal adipose function, forcing the development of insulin resistance. MOTS-c treatment increased brown fat activation and reduced OVX-induced fat accumulation and inflammatory invasion in white adipose tissue, which contributes to the lower level of fatty acid in serum and liver. Moreover, MOTS-c activated AMPK pathway to improve energy dissipation and insulin sensitivity. And a blocker of AMPK pathway was found to attenuate the role of MOTS-c in the regulation of adipocyte lipid metabolism. In conclusion, MOTS-c is a high potential candidate for chronic treatment of menopausal induced metabolic dysfunction. KEY MESSAGES: • MOTS-c prevents ovariectomy (OVX)-induced body weight gain and insulin resistance. • MOTS-c reduces fat mass and suppresses inflammatory response under OVX condition. • MOTS-c sustains the activity of the brown adipose under OVX condition. • MOTS-c mediates AMPK pathway activation to control adipose metabolic homeostasis.

Hypothalamic gene transfer of BDNF promotes healthy aging in mice.

The aging process and age‐related diseases all involve perturbed energy adaption and impaired ability to cope with adversity. Brain‐derived neurotrophic factor (BDNF) in the hypothalamus plays important role in regulation of energy balance. Our previous studies show that recombinant adeno‐associated virus (AAV)‐mediated hypothalamic BDNF gene transfer alleviates obesity, diabetes, and metabolic syndromes in both diet‐induced and genetic models. Here we examined the efficacy and safety of a built‐in autoregulatory system to control transgene BDNF expression mimicking the body's natural feedback systems in middle‐aged mice. Twelve‐month‐old mice were treated with either autoregulatory BDNF vector or yellow fluorescence protein (YFP) control, maintained on normal diet, and monitored for 28 weeks. BDNF gene transfer prevented the development of aging‐associated metabolic declines characterized by: preventing aging‐associated weight gain, reducing adiposity, reversing the decline of brown fat activity, increasing adiponectin while reducing leptin and insulin in circulation, improving glucose tolerance, increasing energy expenditure, alleviating hepatic steatosis, and suppressing inflammatory genes in the hypothalamus and adipose tissues. Moreover, BDNF treatment reduced anxiety‐like and depression‐like behaviors. These safety and efficacy data provide evidence that hypothalamic BDNF is a target for promoting healthy aging.

Type 2 diabetes and metabolic syndrome: identification of the molecular mechanisms, key signaling pathways and transcription factors aimed to reveal new therapeutical targets

Type 2 diabetes mellitus (T2DM) is a socially important disease with only symptomatic therapy developed due to lack of knowledge about its pathogenesis and underlying mechanism. Insulin resistance (IR) is the first link of T2DM pathogenesis and results in decrease of ability of insulin to stimulate glucose uptake by target cells. Development of IR involves genetic predisposition, excessive nutrition, stress, obesity or chronic inflammation due to disruption of insulin signaling within cells. Molecular mechanisms and markers of IR are characterized rather poorly, which prevents early diagnosis and creation of preventive therapy. Euglycemic clamp test is still a golden standard for IR diagnosis in clinic. Hyperglycemia is a distant consequence of IR in which damaging effect of oxidative and carbonyl stress is realized and diagnosis of T2DM is stipulated. Molecular chaperones and small heat-shock proteins have a protective effect at the early stages of T2DM pathogenesis, preventing development of reticulum stress and apoptosis. Endothelial dysfunction is related to T2DM and its cardiovascular complications, however, it is unknown on which stage of pathogenesis these changes occur and what are their molecular inductors. Finally, transcriptional activity and adipogenic differentiation play an important role in formation of new fat depots from predecessor cells and activation of brown and beige fat demonstrating hypolipidemic and hypoglycemic properties. The aim of this study was investigation of pathophysiological mechanisms of development of IR and endothelial dysfunction, role of transcription factor Prep1 and small heat shock proteins, evaluation of novel methods of diagnostics of IR and therapeutic potential of brown and beige fat, determination of biotargets for new antidiabetic drugs.

Binding Efficacy and Thermogenic Efficiency of Pungent and Nonpungent Analogs of Capsaicin.

(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.

Bile acid sequestrant colesevelam enhances beneficial effects of brown fat activation on cholesterol metabolism in APOE*3-Leiden.CETP mice

Bile acid sequestrant colesevelam enhances beneficial effects of brown fat activation on cholesterol metabolism in APOE*3-Leiden.CETP mice

Inflammation of brown/beige adipose tissues in obesity and metabolic disease.

Many of the comorbidities of obesity, including type 2 diabetes and cardiovascular diseases, are related to the low-grade chronic inflammation of white adipose tissue. Under white adipocyte stress, local infiltration of immune cells and enhanced production of pro-inflammatory cytokines together reduce metabolic flexibility and lead to insulin resistance in obesity. Whereas white adipocytes act in energy storage, brown and beige adipocytes specialize in energy expenditure. Brown and beige activity protects against obesity and associated metabolic disorders, such as hyperglycaemia and hyperlipidaemia. Compared to white fat, brown adipose tissue depots are less susceptible to developing local inflammation in response to obesity; however, strong obesogenic insults ultimately induce a locally pro-inflammatory environment in brown fat. This condition directly alters the thermogenic activity of brown fat by impairing its energy expenditure mechanism and uptake of glucose for use as a fuel substrate. Pro-inflammatory cytokines also impair beige adipogenesis, which occurs mainly in subcutaneous adipose tissue. There is evidence that inflammatory processes occurring in perivascular adipose tissues alter their brown-versus-white plasticity, impair the extent of browning in these depots and favour the local release of vasculature damaging signals. In summary, the targeting of brown and beige adipose tissues by pro-inflammatory signals and the subsequent impairment of their thermogenic and metabolite draining activities appears to represent obesity-driven disturbances that contribute to metabolic syndrome and cardiovascular alterations in obesity.

Hepatic tristetraprolin promotes insulin resistance through RNA destabilization of FGF21.

The role of posttranscriptional metabolic gene regulatory programs in diabetes is not well understood. Here, we show that the RNA-binding protein tristetraprolin (TTP) is reduced in the livers of diabetic mice and humans and is transcriptionally induced in response to insulin treatment in murine livers in vitro and in vivo. Liver-specific Ttp-KO (lsTtp-KO) mice challenged with high-fat diet (HFD) have improved glucose tolerance and peripheral insulin sensitivity compared with littermate controls. Analysis of secreted hepatic factors demonstrated that fibroblast growth factor 21 (FGF21) is posttranscriptionally repressed by TTP. Consistent with increased FGF21, lsTtp-KO mice fed HFD have increased brown fat activation, peripheral tissue glucose uptake, and adiponectin production compared with littermate controls. Downregulation of hepatic Fgf21 via an adeno-associated virus-driven shRNA in mice fed HFD reverses the insulin-sensitizing effects of hepatic Ttp deletion. Thus, hepatic TTP posttranscriptionally regulates systemic insulin sensitivity in diabetes through liver-derived FGF21.

CRISPR-Engineered Human Brown-Like Adipocytes Promotes Metabolic Homeostasis through Activation of Endogenous Brown Fat

Brown and brown-like beige adipocytes dissipate energy for thermogenesis and have been proposed to combat obesity and metabolic disorders. Uncoupling protein 1 (UCP1) is uniquely expressed in brown and beige adipocytes, and facilitates fuel utilization and energy expenditure. Ectopic UCP1 overexpression improves obesity and insulin resistance in mice. Recently, we utilized the CRISPR/Cas9 synergistic activation mediator and specific gRNAs to boost endogenous UCP1 expression in human white adipocytes. The CRISPR/Cas9 engineered human brown fat-like (referred to as HUMBLE, hereafter) cells had acquired human brown fat features when comparing bona fide human brown adipocytes derived from the same individual. Obese mice receiving a transplantation of HUMBLE cells showed improved glucose tolerance and insulin sensitivity, as well as increased energy expenditure. This was mediated, at least in part, via activation of endogenous brown fat, which showed an increase in heat production and glucose uptake in mice receiving HUMBLE cells. Co-culture with HUMBLE cells or treatment of conditional medium from HUMBLE cells promoted glucose uptake and thermogenesis in brown adipocytes. Metabolomic analysis identified an increased ratio of arginine and asymmetrical dimethylarginine (ADMA) in the sera of mice receiving HUMBLE cell transplantation. Arginine is known to promote nitric oxide biosynthesis, which can activate thermogenic function of brown fat. Consistently, the level of nitric oxide was increased in the endogenous brown fat of mice receiving HUMBLE cells. Inhibition of nitric oxide synthase abolished the HUMBLE cells-mediated activation of brown adipocytes in vitro and in vivo. In summary, CRISPR/Cas9-mediated activation of endogenous UCP1 expression in human white adipocytes creates brown fat-like features, and activates endogenous brown fat, potentially through arginine-related metabolites to improve the systemic glucose utilization. Disclosure C. Wang: None. M. Lundh: None. R. Kriszt: Employee; Self; QuintilesIMS. T. Huang: None. L.O. Leiria: None. F. Shamsi: None. M. Lynes: None. J. Darcy: None. B. Emanuelli: None. M. Kiebish: None. Y. Tseng: Other Relationship; Self; Chugai Pharmaceutical Co., Ltd.. Research Support; Self; MedImmune.

Rationale and design of a multicentre, randomized, placebo-controlled trial of mirabegron, a Beta3-adrenergic receptor agonist on left ventricular mass and diastolic function in patients with structural heart disease Beta3-left ventricular hypertrophy (Beta3-LVH).

AimsProgressive left ventricular (LV) remodelling with cardiac myocyte hypertrophy, myocardial fibrosis, and endothelial dysfunction plays a key role in the onset and progression of heart failure with preserved ejection fraction. The Beta3‐LVH trial will test the hypothesis that the β3 adrenergic receptor agonist mirabegron will improve LV hypertrophy and diastolic function in patients with hypertensive structural heart disease at high risk for developing heart failure with preserved ejection fraction.Methods and resultsBeta3‐LVH is a randomized, placebo‐controlled, double‐blind, two‐armed, multicentre, European, parallel group study. A total of 296 patients will be randomly assigned to receive either mirabegron 50 mg daily or placebo over 12 months. The main inclusion criterion is the presence of LV hypertrophy, that is, increased LV mass index (LVMi) or increased wall thickening by echocardiography. The co‐primary endpoints are a change in LVMi by cardiac magnetic resonance imaging and a change in LV diastolic function (assessed by the E/e′ ratio). Secondary endpoints include mirabegron's effects on cardiac fibrosis, left atrial volume index, maximal exercise capacity, and laboratory markers. Two substudies will evaluate mirabegron's effect on endothelial function by pulse amplitude tonometry and brown fat activity by positron emission tomography using 17F‐fluorodeoxyglucose. Morbidity and mortality as well as safety aspects will also be assessed.ConclusionsBeta3‐LVH is the first large‐scale clinical trial to evaluate the effects of mirabegron on LVMi and diastolic function in patients with LVH. Beta3‐LVH will provide important information about the clinical course of this condition and may have significant impact on treatment strategies and future trials in these patients.

White- and Brown-Rice Supplementation Improves Insulin Tolerance, Brown Fat Activation, Energy Expenditure, and Changes the Gut Microflora in Diet-Induced Obesity

Increased consumption of white rice (WR) with parallel decreased use of brown rice (BR) have been associated with increased prevalence of type 2 diabetes (T2DM), suggesting WR may elevate the risk of T2DM. To test whether WR or BR have differential effects on glucose metabolism in diet-induced obesity, C57BL/6 mice were fed 6 different diets: control diet (CD, 10%), high fat diet (HFD, 46%) and CD and HFD with either WR or BR. Diets with WR or BR were controlled with comparable carbohydrate and protein contents. After 18 weeks, the median weights of HFD mice were greater (36%) than those on CD. Surprisingly, adding WR or BR to HFD decreased weight gains equally by 53% with parallel reduction of abdominal, visceral, subcutaneous, and total fat vs. HFD. Activity and food intake did not change among mice on HFD. However, HFD decreased heat, VO2, and VCO2 production vs. CD which were normalized by adding WR or BR, per indirect calorimetry with metabolic cages. Intraperitoneal glucose tolerance test on HFD were improved by either WR or BR, although mice on BR+HFD exhibited greater improvements than mice on WR+HFD (P<0.05). Adding WR or BR to HFD decreased HFD-induced elevations of plasma leptin and MCP-1 levels. HFD decreased brown fat tissue mass and markers, UCP-1 and PGC1α vs. CD mice which improved when WR or BR was added to HFD. Gut microbiota composition, assessed by 16S rRNA sequencing and metagenomic analysis, showed clear differences between HFD vs. CD or vs. the addition of BR or WR. The ratio of Firmicutes to Bacteroidetes was increased significantly in HFD vs. CD diet, which has been associated with obesity and metabolic syndrome, but decreased by the addition of WR (63%) or BR (81%). Thus, BR and, surprisingly, WR may activate BAT, increase energy expenditure to reduce body weight and improve insulin sensitivity while on HFD, possibly by altering gut microbiome, indicating that common substances may exist in BR and WR to lower the risks for T2DM. Disclosure H. Yokomizo: None. A. Ishikado: Employee; Self; Sunstar Inc.. Employee; Spouse/Partner; Sunstar Inc.. T. Shinjo: None. K. Park: None. Y. Maeda: None. I. Wu: None. D.M. Pober: None. S. Devkota: None. M. Matsumoto: Employee; Self; Sunstar Inc.. A. Kostic: None. G.L. King: Research Support; Self; Sanofi-Aventis.

NFIA Colocalizes with PPARgamma and Activates the Cell-Type–Specific Enhancers to Control the Brown Fat Gene Program

Brown fat dissipates energy as heat by means of the uncoupling protein-1 (UCP1) on the mitochondrial inner membrane. Brown fat activity is inversely correlated with body mass index in humans, and pilot studies have shown that interventions such as chronic cold exposure successfully recruit human brown fat and increase systemic energy expenditure. Therefore, stimulating development and/or function of brown fat would be a novel strategy for the treatment of obesity and its complications. Here, we identified nuclear factor I-A (NFIA) as a transcriptional regulator of brown fat by a genome-wide open chromatin analysis of murine brown and white fat followed by motif analysis of the brown-fat-specific open chromatin regions. Introduction of NFIA into myoblasts results in brown adipocyte differentiation. Conversely, the brown fat of NFIA knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. In human brown fat, expression of NFIA and the brown-fat-specific genes including UCP1 is positively correlated. Mechanistically, NFIA co-localizes with the master transcriptional regulator of adipogenesis, PPARgamma, selectively at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARgamma, leading to increased chromatin accessibility and active transcription. Most recently, we performed mass spectrometry analysis of NFIA protein complex to identify and characterize the crucial partner of NFIA-dependent brown-fat-specific chromatin regulation. Collectively, these results indicate that NFIA is a key transcription factor that activates the cell-type-specific enhancers and facilitates the binding of PPARgamma for controlling the brown fat gene program. Disclosure Y. Hiraike: Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S, Mitsubishi Tanabe Pharma Corporation. H. Waki: Research Support; Self; MSD K.K., Novartis Pharma K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi K.K., Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Takeda PHarmaceutical Co., Ltd.. S. Tsutsumi: None. H. Aburatani: None. T. Yamauchi: Research Support; Self; Novo Nordisk Inc., Daiichi Sankyo Company, Limited, Sanofi, Takeda, Tanabe-Mitsubishi. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.

In vivo metabolic imaging and monitoring of brown and beige fat.

Activation of the thermogenic brown and beige fat is an effective means to increasing whole-body energy expenditure. In this work, a unique label-free method was developed to quantitatively assess the metabolism and thermogenesis of mouse adipose tissues in vivo. Specifically, an optical redox ratio (ORR) based on the endogenous fluorescence of mitochondrial metabolic coenzymes (nicotinamide adenine dinucleotide and flavin adenine dinucleotide) was used to measure the metabolic state of adipocytes. Our findings demonstrate that the ORR provides a label-free and real-time biomarker to determine the thermogenic response of brown, beige and white adipose tissues to a variety of physiological stimulations. In addition, the redox ratio also can be used to evaluate the degree of browning in the white fat of cold-acclimated mice. This technique is important to understand the recruitment and activation of thermogenic adipocytes in mammals and thus can help to develop therapeutic strategies against obesity.

Identification of a high affinity binding site for abscisic acid on human lanthionine synthetase component C-like protein 2.

Lanthionine synthetase component C-like protein 2 (LANCL2) has been identified as the mammalian receptor mediating the functional effects of the universal stress hormone abscisic acid (ABA) in mammals. ABA stimulates insulin independent glucose uptake in myocytes and adipocytes via LANCL2 binding in vitro, improves glucose tolerance in vivo and induces brown fat activity in vitro and in vivo. The emerging role of the ABA/LANCL2 system in glucose and lipid metabolism makes it an attractive target for pharmacological interventions in diabetes mellitus and the metabolic syndrome. The aim of this study was to investigate the presence of ABA binding site(s) on LANCL2 and identify the amino acid residues involved in ABA binding. Equilibrium binding assays ([3H]-ABA saturation binding and surface plasmon resonance analysis) suggested multiple ABA-binding sites, prompting us to perform a computational study that indicated one putative high-affinity and two low-affinity binding sites. Site-directed mutagenesis (single mutant R118I, triple mutants R118I/R22I/K362I and R118I/S41A/E46I) and equilibrium binding experiments on the mutated LANCL2 proteins identified a high-affinity ABA-binding site involving R118, with a KD of 2.6 nM ± 1.2 nM, as determined by surface plasmon resonance. Scatchard plot analysis of binding curves from both types of equilibrium binding assays revealed a Hill coefficient >1, suggesting cooperativity of ABA binding to LANCL2. Identification of the high-affinity ABA-binding site is expected to allow the design of ABA agonists/antagonists, which will help to understand the role of the ABA/LANCL2 system in human physiology and disease.

Brown Adipokines.

Brown adipokines are regulatory factors secreted by brown and beige adipocytes that exhibit endocrine, paracrine, and autocrine actions. Peptidic and non-peptidic molecules, including miRNAs and lipids, are constituents of brown adipokines. Brown adipose tissue remodeling to meet thermogenic needs is dependent on the secretory properties of brown/beige adipocytes. The association between brown fat activity and a healthy metabolic profile, in relation to energy balance and glucose and lipid homeostasis, is influenced by the endocrine actions of brown adipokines. A comprehensive knowledge of the brown adipocyte secretome is still lacking. Advancements in the identification and characterization of brown adipokines will facilitate therapeutic interventions for metabolic diseases, as these molecules are obvious candidates to therapeutic agents. Moreover, identification of brown adipokines as circulating biomarkers of brown adipose tissue activity may be particularly useful for noninvasive assessment of brown adipose tissue alterations in human pathologies.

Peroxisome Proliferator Activated Receptor Gamma Controls Mature Brown Adipocyte Inducibility through Glycerol Kinase

Peroxisome proliferator-activated receptors (PPARs) have been suggested as the master regulators ofadipose tissue formation. However, their role in regulating brown fat functionality has not been resolved. To address this question, we generated mice with inducible brown fat-specific deletions of PPARα, β/δ, and γ, respectively. We found that both PPARα and β/δδ are dispensable for brown fat function. In contrast, we could show that ablation of PPARγ invitro and invivo led to a reduced thermogenic capacity accompanied by a loss of inducibility by β-adrenergic signaling, as well as a shift from oxidative fatty acid metabolism to glucose utilization. We identified glycerol kinase (Gyk) as a partial mediator of PPARγ function and could show that Gyk expression correlates with brown fat thermogenic capacity in human brown fat biopsies. Thus, Gyk might constitute the link between PPARγ-mediated regulation of brown fat function and activation by β-adrenergic signaling.

Translational Aspects of Brown Fat Activation by Food-Derived Stimulants.

Since the rediscovery of brown adipose tissue (BAT) in humans, its energy-dissipating ability has been well-recognized. The negative correlations of BAT activity with adiposity and insulin sensitivity provided an obvious rationale for discerning reliable and practical strategies for stimulating BAT. Though cold exposure or use of pharmacological adrenomimetics can activate BAT, they may have adverse effects. Therefore, determining alternative stimulants of BAT with lower risks such as commonly used food ingredients is highly desirable. Recent observations revealed that chemical activation of temperature-sensitive transient receptor potential (TRP) channels by food ingredients can recruit BAT in humans. Furthermore, animal studies have identified several food-derived stimulants of BAT acting through multiple mechanisms distinct from a TRP-mediated process. Dietary compounds acting as an activator of Sirtuin 1, a critical regulator of mitochondrial biogenesis and brown adipocyte differentiation, are one such class of promising food-derived BAT activators in humans. While the individual effects of various dietary factors are increasingly established in a laboratory setting, the potential synergistic effects of multiple stimulants on BAT remain to be tested in a clinical environment. These investigations may support the development of efficient, flexible dietary regimens capable of boosting BAT thermogenesis.

Effects of heat and cold on health, with special reference to Finnish sauna bathing.

Environmental stress such as extremely warm or cold temperature is often considered a challenge to human health and body homeostasis. However, the human body can adapt relatively well to heat and cold environments, and recent studies have also elucidated that particularly heat stress might be even highly beneficial for human health. Consequently, the aim of the present brief review is first to discuss general cardiovascular and other responses to acute heat stress, followed by a review of beneficial effects of Finnish sauna bathing on general and cardiovascular health and mortality as well as dementia and Alzheimer's disease risk. Plausible mechanisms included are improved endothelial and microvascular function, reduced blood pressure and arterial stiffness, and possibly increased angiogenesis in humans, which are likely to mediate the health benefits of sauna bathing. In addition to heat exposure with physiological adaptations, cold stress-induced physiological responses and brown fat activation on health are also discussed. This is important to take into consideration, as sauna bathing is frequently associated with cooling periods in cold(er) environments, but their combination remains poorly investigated. We finally propose, therefore, that possible additive effects of heat- and cold-stress-induced adaptations and effects on health would be worthy of further investigation.

Fucoxanthin and Its Metabolite Fucoxanthinol Do Not Induce Browning in Human Adipocytes.

Rodent studies suggest that the antiobesity effects of fucoxanthin relate to activation of brown fat and conversion of white adipocytes to the brown phenotype. Toevaluate the browning effect in human adipocytes, we investigated the genes involved in browning and measured the oxygen consumption rate (OCR). Data were analyzed by one way ANOVA. Relative to control, fucoxanthinol (1 μM, 0.1 μM, 0.01 μM, 1 nM, 0.1 nM), the metabolite present in human plasma, stimulated lipolysis acutely (mean ± SEM: 4.2 ± 0.8, 3.1 ± 0.6, 4.1 ± 0.9, 3.8 ± 0.7, 3.8 ± 0.7, respectively, p < 0.01). There was no effect on OCR or the mRNA expression of UCP1, CPT-1β, and GLUT4, the genes associated with browning of adipose tissue, when human adipocytes were treated with fucoxanthin or fucoxanthinol. -mRNA expression of PGC-1α, PPARα, PPARγ, PDK4, FAS, and the lipolytic enzymes was not significantly altered by fucoxanthinol treatment (p > 0.05). Thus, in human adipocytes, fucoxanthin and its metabolite do not stimulate conversion of white adipocytes to the brown phenotype.

SYK kinase mediates brown fat differentiation and activation

Brown adipose tissue (BAT) metabolism influences glucose homeostasis and metabolic health in mice and humans. Sympathetic stimulation of β-adrenergic receptors in response to cold induces proliferation, differentiation, and UCP1 expression in pre-adipocytes and mature brown adipocytes. Here we show that spleen tyrosine kinase (SYK) is upregulated during brown adipocyte differentiation and activated by β-adrenergic stimulation. Deletion or inhibition of SYK, a kinase known for its essential roles in the immune system, blocks brown and white pre-adipocyte proliferation and differentiation in vitro, and results in diminished expression of Ucp1 and other genes regulating brown adipocyte function in response to β-adrenergic stimulation. Adipocyte-specific SYK deletion in mice reduces BAT mass and BAT that developed consisted of SYK-expressing brown adipocytes that had escaped homozygous Syk deletion. SYK inhibition in vivo represses β-agonist-induced thermogenesis and oxygen consumption. These results establish SYK as an essential mediator of brown fat formation and function.