Brown Adipose Tissue Thermogenesis Research Articles

The histone methyltransferase SUV420H2 regulates brown and beige adipocyte thermogenesis.

Activation of brown adipose tissue (BAT) thermogenesis increases energy expenditure and alleviates obesity. Here we discover that histone methyltransferase suppressor of variegation 4-20 homolog 2 (Suv420h2) expression parallels that of Ucp1 in brown and beige adipocytes and that Suv420h2 knockdown significantly reduces, whereas Suv420h2 overexpression significantly increases Ucp1 levels in brown adipocytes. Suv420h2 knockout (H2KO) mice exhibit impaired cold-induced thermogenesis and are prone to diet-induced obesity. In contrast, mice with specific overexpression of Suv420h2 in adipocytes display enhanced cold-induced thermogenesis and are resistant to diet-induced obesity. Further study shows that Suv420h2 catalyzes H4K20 trimethylation at eukaryotic translation initiation factor 4E-binding protein 1 (4e-bp1) promoter, leading to down-regulated expression of 4e-bp1, a negative regulator of the translation initiation complex. This in turn up-regulates PGC1α protein levels, which is associated with increased expression of thermogenic program. We conclude that Suv420h2 is a key regulator of brown/beige adipocyte development and thermogenesis.

Thermoregulatory pathway underlying the pyrogenic effects of prostaglandin E2 in the lateral parabrachial nucleus of male rats.

It has been shown that prostaglandin (PG) E2 synthesized in the lateral parabrachial nucleus (LPBN) is involved in lipopolysaccharide-induced fever. But the neural mechanisms of how intra-LPBN PGE2 induces fever remain unclear. In this study, we investigated whether the LPBN-preoptic area (POA) pathway, the thermoafferent pathway for feed-forward thermoregulatory responses, mediates fever induced by intra-LPBN PGE2 in male rats. The core temperature (Tcore) was monitored using a temperature radiotelemetry transponder implanted in rat abdomen. We showed that microinjection of PGE2 (0.28 nmol) into the LPBN significantly enhanced the density of c-Fos-positive neurons in the median preoptic area (MnPO). The chemical lesioning of MnPO with ibotenate or selective genetic lesioning or inhibition of the LPBN-MnPO pathway significantly attenuated fever induced by intra-LPBN injection of PGE2. We demonstrated that EP3 receptor was a pivotal receptor for PGE2-induced fever, since microinjection of EP3 receptor agonist sulprostone (0.2 nmol) or EP3 receptor antagonist L-798106 (2 nmol) into the LPBN mimicked or weakened the pyrogenic action of LPBN PGE2, respectively, but this was not the case for EP4 and EP1 receptors. Whole-cell recording from acute LPBN slices revealed that the majority of MnPO-projecting neurons originating from the external lateral (el) and dorsal (d) LPBN were excited and inhibited, respectively, by PGE2 perfusion, initiating heat-gain and heat-loss mechanisms. The amplitude but not the frequency of spontaneous and miniature glutamatergic excitatory postsynaptic currents (sEPSCs and mEPSCs) in MnPO-projecting LPBel neurons increased after perfusion with PGE2; whereas the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) and the A-type potassium (IA) current density did not change. In MnPO-projecting LPBd neurons, neither sEPSCs nor sIPSCs responded to PGE2; however, the IA current density was significantly increased by PGE2 perfusion. These electrophysiological responses and the thermoeffector reactions to intra-LPBN PGE2 injection, including increased brown adipose tissue thermogenesis, shivering, and decreased heat dissipation, were all abolished by L-798106, and mimicked by sulprostone. These results suggest that the pyrogenic effects of intra-LPBN PGE2 are mediated by both the inhibition of the LPBd-POA pathway through the EP3 receptor-mediated activation of IA currents and the activation of the LPBel-POA pathway through the selective enhancement of glutamatergic synaptic transmission via EP3 receptors.

A versatile delivery vehicle for cellular oxygen and fuels, or metabolic sensor? - A review and perspective on the functions of myoglobin.

A canonical view of the primary physiological function of myoglobin (Mb) is that it is an oxygen (O2) storage protein supporting mitochondrial oxidative phosphorylation, especially as the tissue O2 partial pressure (pO2) drops and Mb offloads O2. Besides O2 storage/transport, recent findings support functions for Mb in lipid trafficking and sequestration, interacting with cellular glycolytic metabolites such as lactate (LAC) and pyruvate (PYR) , and "ectopic" expression in some types of cancer cells and in brown adipose tissue (BAT). Data from Mb knockout (Mb-/-) mice and biochemical models suggest additional metabolic roles for Mb, especially regulation of nitric oxide (NO) pools, modulation of BAT bioenergetics, thermogenesis, and lipid storage phenotypes. From these and other findings in the literature over many decades, Mb's function is not confined to delivering O2 in support of oxidative phosphorylation, but also to serve as an O2-sensor that modulates intracellular pO2- and NO-responsive molecular signaling pathways. This paradigm reflects a fundamental change in how oxidative metabolism and cell regulation are viewed in Mb-expressing cells such as skeletal muscle, heart, brown adipocytes, and select cancer cells. Herein, we review historic and emerging views related to the physiological roles for Mb, and present working models illustrating the possible importance of interactions between Mb, gases, and small molecule metabolites in regulation of cell signaling and bioenergetics.

Oral supplementation with resveratrol improves hormonal profile and increases expression of genes associated with thermogenesis in oophorectomy mice

Menopause causes important bodily and metabolic changes, which favor the increased occurrence of cardiovascular diseases, obesity, diabetes, and osteoporosis. Resveratrol exerts proven effects on body metabolism, improving glucose and lipid homeostasis and reducing inflammation and oxidative stress in various organs and tissues. Accordingly, this study evaluates the effects of resveratrol supplementation on the expression of markers associated with thermogenesis in brown adipose tissue, and on the body, metabolic and hormonal parameters of female mice submitted to bilateral oophorectomy. Eighteen female mice were randomized into three groups: G1: control (CONTROL), G2: oophorectomy (OOF), and G3: oophorectomy + resveratrol (OOF+RSV); the animals were kept under treatment for twelve weeks, being fed a standard diet and treated with resveratrol via gavage. Body, biochemical, hormonal, and histological parameters were measured; in addition to the expression of markers associated with thermogenesis in brown adipose tissue. The results showed that animals supplemented with resveratrol showed reduced body weight and visceral adiposity, in addition to glucose, total cholesterol, and triglyceride levels; decreased serum FSH levels and increased estrogen levels were observed compared to the OOF group and mRNA expression of PRDM16, UCP1, and SIRT3 in brown adipose tissue. The findings of this study suggest the important role of resveratrol in terms of improving body, metabolic, and hormonal parameters, as well as modulating markers associated with thermogenesis in brown adipose tissue of female mice submitted to oophorectomy.

Ventromedial hypothalamic nucleus subset stimulates tissue thermogenesis via preoptic area outputs

ObjectiveHypothalamic signals potently stimulate energy expenditure by engaging peripheral mechanisms to restore energy homeostasis. Previous studies have identified several critical hypothalamic sites (e.g. preoptic area (POA) and ventromedial hypothalamic nucleus (VMN)) that could be part of an interconnected neurocircuit that controls tissue thermogenesis and essential for body weight control. However, the key neurocircuit that can stimulate energy expenditure has not yet been established. MethodsHere, we investigated the downstream mechanisms by which VMN neurons stimulate adipose tissue thermogenesis. We manipulated subsets of VMN neurons acutely as well as chronically and studied its effect on tissue thermogenesis and body weight control, using Sf1Cre and Adcyap1Cre mice and measured physiological parameters under both high-fat diet and standard chow diet conditions. To determine the node efferent to these VMN neurons, that is involved in modulating energy expenditure, we employed electrophysiology and optogenetics experiments combined with measurements using tissue-implantable temperature microchips. ResultsActivation of the VMN neurons that express the steroidogenic factor 1 (Sf1; VMNSf1 neurons) reduced body weight, adiposity and increased energy expenditure in diet-induced obese mice. This function is likely mediated, at least in part, by the release of the pituitary adenylate cyclase-activating polypeptide (PACAP; encoded by the Adcyap1 gene) by the VMN neurons, since we previously demonstrated that PACAP, at the VMN, plays a key role in energy expenditure control. Thus, we then shifted focus to the subpopulation of VMNSf1 neurons that contain the neuropeptide PACAP (VMNPACAP neurons). Since the VMN neurons do not directly project to the peripheral tissues, we traced the location of the VMNPACAP neurons' efferents. We identified that VMNPACAP neurons project to and activate neurons in the caudal regions of the POA whereby these projections stimulate tissue thermogenesis in brown and beige adipose tissue. We demonstrated that selective activation of caudal POA projections from VMNPACAP neurons induces tissue thermogenesis, most potently in negative energy balance and activating these projections lead to some similar, but mostly unique, patterns of gene expression in brown and beige tissue. Finally, we demonstrated that the activation of the VMNPACAP neurons' efferents that lie at the caudal POA are necessary for inducing tissue thermogenesis in brown and beige adipose tissue. ConclusionsThese data indicate that VMNPACAP connections with the caudal POA neurons impact adipose tissue function and are important for induction of tissue thermogenesis. Our data suggests that the VMNPACAP → caudal POA neurocircuit and its components are critical for controlling energy balance by activating energy expenditure and body weight control.

Smooth muscle cell derived Cxcl12 directs macrophage accrual and sympathetic innervation to control thermogenic adipose tissue

Sympathetic innervation of brown adipose tissue (BAT) controls mammalian adaptative thermogenesis. However, the cellular and molecular underpinnings contributing to BAT innervation remain poorly defined. Here, we show that smooth muscle cells (SMCs) support BAT growth, lipid utilization, and thermogenic plasticity. Moreover, we find that BAT SMCs express and control the bioavailability of Cxcl12. SMC deletion of Cxcl12 fosters brown adipocyte lipid accumulation, reduces energy expenditure, and increases susceptibility to diet-induced metabolic dysfunction. Mechanistically, we find that Cxcl12 stimulates CD301+ macrophage recruitment and supports sympathetic neuronal maintenance. Administering recombinant Cxcl12 to obese mice or leptin-deficient (Ob/Ob) mice is sufficient to boost macrophage presence and drive sympathetic innervation to restore BAT morphology and thermogenic responses. Altogether, our data reveal an SMC chemokine-dependent pathway linking immunological infiltration and sympathetic innervation as a rheostat for BAT maintenance and thermogenesis.

BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis

Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.

Genetic evidence for involvement of β2-adrenergic receptor in brown adipose tissue thermogenesis in humans.

Sympathetic activation of brown adipose tissue (BAT) thermogenesis can ameliorate obesity and related metabolic abnormalities. However, crucial subtypes of the β-adrenergic receptor (AR), as well as effects of its genetic variants on functions of BAT, remains unclear in humans. We conducted association analyses of genes encoding β-ARs and BAT activity in human adults. Single nucleotide polymorphisms (SNPs) in β1-, β2-, and β3-AR genes (ADRB1, ADRB2, and ADRB3) were tested for the association with BAT activity under mild cold exposure (19 °C, 2 h) in 399 healthy Japanese adults. BAT activity was measured using fluorodeoxyglucose-positron emission tomography and computed tomography (FDG-PET/CT). To validate the results, we assessed the effects of SNPs in the two independent populations comprising 277 healthy East Asian adults using near-infrared time-resolved spectroscopy (NIRTRS) or infrared thermography (IRT). Effects of SNPs on physiological responses to intensive cold exposure were tested in 42 healthy Japanese adult males using an artificial climate chamber. We found a significant association between a functional SNP (rs1042718) in ADRB2 and BAT activity assessed with FDG-PET/CT (p < 0.001). This SNP also showed an association with cold-induced thermogenesis in the population subset. Furthermore, the association was replicated in the two other independent populations; BAT activity was evaluated by NIRTRS or IRT (p < 0.05). This SNP did not show associations with oxygen consumption and cold-induced thermogenesis under intensive cold exposure, suggesting the irrelevance of shivering thermogenesis. The SNPs of ADRB1 and ADRB3 were not associated with these BAT-related traits. The present study supports the importance of β2-AR in the sympathetic regulation of BAT thermogenesis in humans. The present collection of DNA samples is the largest to which information on the donor's BAT activity has been assigned and can serve as a reference for further in-depth understanding of human BAT function.

MAFB in macrophages regulates cold-induced neuronal density in brown adipose tissue

Transcription factor MAFB regulates various homeostatic functions of macrophages. This study explores the role of MAFB in brown adipose tissue (BAT) thermogenesis using macrophage-specific Mafb-deficient (Mafbf/f::LysM-Cre) mice. We find that Mafb deficiency in macrophages reduces thermogenesis, energy expenditure, and sympathetic neuron (SN) density in BAT under cold conditions. This phenotype features a proinflammatory environment that is characterized by macrophage/granulocyte accumulation, increases in interleukin-6 (IL-6) production, and IL-6 trans-signaling, which lead to decreases in nerve growth factor (NGF) expression and reduction in SN density in BAT. We confirm MAFB regulation of IL-6 expression using luciferase readout driven by IL-6 promoter in RAW-264.7 macrophage cell lines. Immunohistochemistry shows clustered organization of NGF-producing cells in BAT, which are primarily TRPV1+ vascular smooth muscle cells, as additionally shown using single-cell RNA sequencing and RT-qPCR of the stromal vascular fraction. Treating Mafbf/f::LysM-Cre mice with anti-IL-6 receptor antibody rescues SN density, body temperature, and energy expenditure.

A comparative assessment of reference genes in mouse brown adipocyte differentiation and thermogenesis in vitro

ABSTRACT Adipogenic differentiation and thermogenesis in brown adipose tissue (BAT) undergo dynamic processes, altering phenotypes and gene expressions. Proper reference genes in gene expression analysis are crucial to mitigate experimental variances and ensure PCR efficacy. Unreliable reference genes can lead to erroneous gene expression quantification, resulting in data misinterpretation. This study focused on identifying suitable reference genes for mouse brown adipocyte research, utilizing brown adipocytes from the Ucp1-luciferase ThermoMouse model. Comparative analysis of gene expression data under adipogenesis and thermogenesis conditions was conducted, validating 13 housekeeping genes through various algorithms, including DeltaCq, BestKeeper, geNorm, Normfinder, and RefFinder. Tbp and Rer1 emerged as optimal references for Ucp1 and Pparg expression in brown adipogenesis, while Tbp and Ubc were ideal for the expression analysis of these target genes in thermogenesis. Conversely, certain conventional references, including Actb, Tubb5, and Gapdh, proved unstable as reference genes under both conditions. These findings stress the critical consideration of reference gene selection in gene expression analysis within specific biological systems to ensure accurate conclusions.

Xiasangju alleviate metabolic syndrome by enhancing noradrenaline biosynthesis and activating brown adipose tissue.

Metabolic syndrome (MetS) is a clinical condition associated with multiple metabolic risk factors leading to type 2 diabetes mellitus and other metabolic diseases. Recent evidence suggests that modulating adipose tissue to adaptive thermogenesis may offer therapeutic potential for MetS. Xiasangju (XSJ) is a marketed drug and dietary supplement used for the treatment of metabolic disease with anti-inflammatory activity. This study investigated the therapeutic effects of XSJ and the underlying mechanisms affecting the activation of brown adipose tissue (BAT) in MetS. The results revealed that XSJ ameliorated MetS by enhancing glucose and lipid metabolism, leading to reduced body weight and abdominal circumference, decreased adipose tissue and liver index, and improved blood glucose tolerance. XSJ administration stimulated catecholamine biosynthesis, increasing noradrenaline (NA) levels and activating NA-mediated proteins in BAT. Thus, BAT enhanced thermogenesis and oxidative phosphorylation (OXPHOS). Moreover, XSJ induced changes in gut microbiota composition, with an increase in Oscillibacter abundance and a decrease in Bilophila, Candidatus Stoquefichus, Holdemania, Parasutterella and Rothia. XSJ upregulated the proteins associated with intestinal tight junctions corresponding with lower serum lipopolysaccharide (LPS), tumor necrosis factor α (TNF-α) monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) levels to maintain NA signaling transport. In summary, XSJ may alleviate MetS by promoting thermogenesis in BAT to ultimately boost energy metabolism through increasing NA biosynthesis, strengthening intestinal barrier integrity and reducing low-grade inflammation. These findings suggest XSJ has potential as a natural therapeutic agent for the treatment of MetS.

The effects of the β1-adrenergic receptor antagonist bisoprolol administration on mirabegron-stimulated human brown adipose tissue thermogenesis.

Pharmacological stimulation of human brown adipose tissue (BAT) has been hindered by ineffective activation or undesirable off-target effects. Oral administration of the maximal allowable dose of mirabegron (200 mg), a β3-adrenergic receptor (β3-AR) agonist, has been effective in stimulating BAT thermogenesis and whole-body energy expenditure. However, this has been accompanied by undesirable cardiovascular effects. Therefore, we hypothesized that combining mirabegron with a β1-AR antagonist could suppress these unwanted effects and increase the stimulation of the β3-AR and β2-AR in BAT. We performed a randomized crossover trial (NCT04823442) in 8 lean men. Mirabegron (200 mg) was administered orally with or without the β1-AR antagonist bisoprolol (10 mg). Dynamic [11C]-acetate and 2-deoxy-2-[18F]fluoro-d-glucose PET/CT scans were performed sequentially after oral administration of mirabegron ± bisoprolol. Compared to room temperature, mirabegron alone increased BAT oxidative metabolism (0.84 ± 0.46 vs. 1.79 ± 0.91 min-1, p = 0.0433), but not when combined with bisoprolol. The metabolic rate of glucose in BAT, measured using [18F]FDG PET, was significantly higher with mirabegron than mirabegron with bisoprolol (24 ± 10 vs. 16 ± 8 nmol/g/min, p = 0.0284). Bisoprolol inhibited the mirabegron-induced increase in systolic blood pressure and heart rate. The administration of bisoprolol decreases the adverse cardiovascular effects of mirabegron. However, the provided dose also blunted the mirabegron-stimulated increase in BAT lipolysis, thermogenesis, and glucose uptake. The attenuation in BAT blood flow induced by the large dose of bisoprolol may have limited BAT thermogenesis.

Creatine and low-dose lithium supplementation separately alter energy expenditure, body mass, and adipose metabolism for the promotion of thermogenesis

Nutraceutical approaches to promote adipose tissue thermogenesis may help to prevent obesity onset. Creatine is a critical regulator of adipose metabolic function and low-dose lithium supplementation has been shown to promote adipose thermogenesis. In the present study, we sought to directly compare the two supplements for their effects on adipose metabolism and thermogenesis. We show that both supplements increase daily energy expenditure (EE) and reduce body mass in male Sprague-Dawley rats. Lithium increased brown adipose tissue (BAT) mitochondrial and lipolytic proteins that are associated with thermogenesis, while creatine increased BAT UCP1 and mitochondrial respiration. The BAT thermogenic findings were not observed in females. White adipose tissue and skeletal muscle markers of thermogenesis were unaltered with the supplements. Together, the data show that low-dose lithium and creatine have diverging effects on markers of BAT thermogenesis and that each increase daily EE and lower body mass in a sex-dependent manner.

Mitochondrial flashes are interlinked with adaptive thermogenesis in brown adipocytes

Mitochondrial flash (mitoflash) is the electrochemical excitation of a single mitochondrion and plays diverse signaling roles in a variety of cells. From the viewpoint of bioenergetics, it represents the transient uncoupling of mitochondrial respiration from ATP synthesis. Brown adipose tissue (BAT) produces heat, primarily via mitochondrial uncoupled respiration. Here, we aim to illustrate the mitoflash activity in BAT thermogenesis. We show that BAT mitochondria undergo stochastic and intermittent mitoflashes at the levels of isolated mitochondria, cultured brown adipocytes, and even intact BAT. A BAT mitoflash contains multiple signals, including transient depolarization of mitochondrial membrane potential, transient matrix alkalization, and bursting production of reactive oxygen species. Importantly, thermogenic activation by β3-adrenergic stimulation dramatically augments mitoflash incidence, with mild effects on its unitary characteristics. Ablation of the thermogenic uncoupling protein 1 (UCP1) showed little effect on mitoflash biogenesis during heat production. Collectively, our results suggest that mitoflash might constitute an elemental signaling activity of mitochondria to regulate BAT thermogenesis.

UCP1 and CKB are parallel players in BAT

It is generally believed that the contributions of the UCP1-independent thermogenic pathways are secondary to UCP1-mediated thermogenesis in BAT. Now, Rahbani etal. demonstrate invivo that adaptive thermogenesis in brown adipose tissue is regulated by UCP1 and CKB in parallel.

Mitochondrial biogenesis in white adipose tissue mediated by JMJD1A-PGC-1 axis limits age-related metabolic disease

Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of β-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to β-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.

Effect of Electroacupuncture Stimulation on Brown Adipose Tissue Thermogenesis.

: Brown adipose tissue (BAT) is a unique thermogenic tissue in mammals mediated by uncoupling protein 1 (UCP1). The energy generated by glucose and triglyceride metabolism is released and transmitted throughout the body as heat. Understanding the factors influencing BAT function is crucial to determine its metabolic significance and effects on overall health. Although studies have shown that electroacupuncture (EA) at specific acupoints (e.g., ST36) can stimulate BAT, its effects at other acupoints are not well understood. Further research is needed to investigate the potential effects of EA at these acupoints and their association with BAT activation. : This study aimed to investigate the effects of EA at the GV20 and EX-HN3 acupoints. Specifically, the effects of EA on BAT thermogenesis were analyzed by infrared thermography, western blotting, and real-time polymerase chain reaction (PCR). : A total of 12 C57BL/6J mice were randomly divided into the EA and control groups. The EA group received EA at GV20 and EX-HN3 for 20 min once daily for 14 days. The control group underwent the same procedure but without EA. The core body temperature was monitored. Infrared thermal images of the back of each mouse in both groups were captured. BAT samples were collected after euthanasia to analyze UCP1 protein and UCP1 mRNA. : The average skin temperature in the scapular region of the EA group was increased by 1.1℃ compared with that of the C group (p < 0.05). Additionally, the average temperature along the governor vessel in the EA group was increased by 1.6℃ (p = 0.045). EA significantly increased the expression of UCP1 protein (p = 0.001) and UCP1 mRNA (p = 0.002) in BAT, suggesting a potential link between EA and BAT thermogenesis. : EA induced BAT thermogenesis, suggesting GV20 and EX-HN3 as potential acupoints for BAT stimulation. The experimental results also highlighted unique meridian characteristics as demonstrated by elevated skin temperature along the governor vessel in mice.

Conjugated linoleic acid (CLA) reduces HFD-induced obesity by enhancing BAT thermogenesis and iWAT browning via the CD36-AMPK pathway.

The antiobesity effect of conjugated linoleic acid (CLA) has been reported. However, the underlying mechanisms have not been fully clarified. Thus, this study aimed to investigate the effects of CLA on thermogenesis of interscapular brown adipose tissue (iBAT) and browning of inguinal subcutaneous white adipose tissue (iWAT) and explore the possible signaling pathway. The in vivo results showed that CLA enhanced the O2 consumption and heat production in HFD (high-fat diet)-fed female mice by roughly 38%. Meanwhile, CLA increased the average iBAT temperature by 2°C at the room temperature and cold exposure, respectively. Correspondingly, CLA caused 1.6-and 2.4-fold increases in the expression of UCP1 (uncoupling protein 1) of BAT and iWAT, respectively, suggesting the activated iBAT thermogenesis and iWAT browning in HFD-fed female mice. Meanwhile, CLA could promote the formation of brown and beige adipocytes in differentiated stromal vascular cells (SVCs) isolated from iBAT and iWAT (the expressions of UCP1 were promoted by about twofold changes). In possible mechanisms, CLA stimulated the expression of CD36 and the activation of theAMPK pathway in mice iBAT and iWAT as well as the differentiated SVCs. However, inhibition of CD36 and AMPK (adenosine 5'-monophosphate-activated protein kinase) abolished the promotive effects of CLA on brown and beige adipocytes formation. Hence, we showed that CLA reduced HFD-induced obesity through enhancing iBAT thermogenesis and iWAT browning via theCD36-AMPK pathway.

Antiobesity effects of intestinal gluconeogenesis are mediated by the brown adipose tissue sympathetic nervous system.

Intestinal gluconeogenesis (IGN), via the initiation of a gut-brain nervous circuit, accounts for the metabolic benefits linked to dietary proteins or fermentable fiber in rodents and has been positively correlated with the rapid amelioration of body weight after gastric bypass surgery in humans with obesity. In particular, the activation of IGN moderates the development of hepatic steatosis accompanying obesity. In this study, we investigated the specific effects of IGN on adipose tissue metabolism, independent of its induction by nutritional manipulation. We used two transgenic mouse models of suppression or overexpression of G6pc1, the catalytic subunit of glucose-6 phosphatase, which is the key enzyme of endogenous glucose production specifically in the intestine. Under a hypercaloric diet, mice overexpressing IGN showed lower adiposity and higher thermogenic capacities than wild-type mice, featuring marked browning of white adipose tissue (WAT) and prevention of the whitening of brown adipose tissue (BAT). Sympathetic denervation restricted to BAT caused the loss of the antiobesity effects associated with IGN. Conversely, IGN-deficient mice exhibited an increase in adiposity under a standard diet, which was associated with decreased expression of markers of thermogenesis in both BAT and WAT. IGN is sufficient to activate the sympathetic nervous system and prevent the expansion and the metabolic alterations of BAT and WAT metabolism under a high-calorie diet, thereby preventing the development of obesity. These data increase knowledge of the mechanisms of weight reduction in gastric bypass surgery and pave the way for new approaches to prevent or cure obesity.

Inside the Biology of the β3-Adrenoceptor.

Since the first discovery in 1989, the β3-adrenoceptor (β3-AR) has gained great attention because it showed the ability to regulate many physiologic and metabolic activities, such as thermogenesis and lipolysis in brown and white adipose tissue, respectively (BAT, WAT), negative inotropic effects in cardiomyocytes, and relaxation of the blood vessels and the urinary bladder. The β3-AR has been suggested as a potential target for cancer treatment, both in adult and pediatric tumors, since under hypoxia its upregulation in the tumor microenvironment (TME) regulates stromal cell differentiation, tumor growth and metastases, signifying that its agonism/antagonism could be useful for clinical benefits. Promising results in cancer research have proposed the β3-AR being targeted for the treatment of many conditions, with some drugs, at present, undergoing phase II and III clinical trials. In this review, we report the scientific journey followed by the research from the β3-Ars' discovery, with focus on the β3-Ars' role in cancer initiation and progression that elects it an intriguing target for novel antineoplastic approaches. The overview highlights the great potential of the β3-AR, both in physiologic and pathologic conditions, with the intention to display the possible benefits of β3-AR modulation in cancer reality.