Increased Brown Adipose Tissue Activity Research Articles

FRI488 The Effect Of Thyroid Stimulating Hormone On Brown Adipose Tissue In Humans

Abstract Disclosure: L. Salej: None. S.D. Kodani: None. N. Chaves: None. K.N. Youssef: None. R. Monahan-Earley: None. H. Halle: None. H. Shaelah: None. P. Annie: None. J.A. Parker: None. A.M. Cypess: None. G. Kolodny: None. Y. Tseng: None. B.C. James: None. A. Gavrila-Filip: None. Obesity and diabetes are two main public health concerns due to their high impact on global morbidity and mortality. In an effort to find new treatment strategies, highly active metabolic tissues such as brown adipose tissue (BAT) have been studied as potential targets. Animal studies have shown that TSH may have a direct local effect on BAT mass and activity by stimulating local T3 production via increased deiodinase-2 (DIO2) expression and also by increasing the expression of uncoupling protein-1 (UCP-1), the key molecule in BAT thermogenesis. We hypothesized that high circulating TSH levels could increase BAT activity by increasing local T3 production and generating a local tissue "thyrotoxicosis". We studied 7 patients with thyroid cancer who underwent thyroid surgery and required recombinant TSH (rhTSH) administration for standard follow-up procedures. Each patient underwent 2 PET-CT scans for assessment of BAT volume and activity, first one day after the rhTSH administration (high TSH state) and then 1-3 months later on suppressive thyroid hormone (TH) treatment (low TSH state). Indirect calorimetry and serum thyroid function tests, fasting glucose, insulin, HbA1c, and lipid panel were measured. Our results show that there was a statistically significant difference in TSH levels (p = 0.0095), with stable circulating T4 and T3 between the low and high TSH states. There was no statistically significant difference in the BAT volume and activity (SUVmax) between the high TSH and low TSH states. Age was a significant predictor of BAT SUVmax (p = 0.008; coeff = -0.39, CI = -0.65-0.13), while BMI was a significant predictor for resting energy expenditure (REE) (p = 0.04; coeff = -203.95, CI = -396.12 - -10.78). Based on these findings, along with those from our previous study[1] showing that circulating TH levels may not be directly correlated with BAT function, we have extended our study to assess the intracellular thyroid hormone status in BAT. We have collected deep peri-thyroidal adipose tissue and subcutaneous white adipose tissue (WAT) as a control group from patients undergoing thyroid surgery. In these samples, we will measure mRNA expression of TSH receptors, TH receptors, β-adrenergic receptors, DIO2 and UCP-1 and evaluate for correlations with circulating TSH and TH levels as well as different metabolic parameters to get a deeper insight into BAT function in humans. Reference: 1. Gavrila A et al. Variable Cold-Induced Brown Adipose Tissue Response to Thyroid Hormone Status. Thyroid. 2017 Jan 1;27(1):1-10. Presentation: Friday, June 16, 2023

Mechanisms underlying the efficacy of a rodent model of vertical sleeve gastrectomy — A focus on energy expenditure

ObjectiveBariatric surgery remains the only effective and durable treatment option for morbid obesity. Vertical Sleeve Gastrectomy (VSG) is currently the most widely performed of these surgeries primarily because of its proven efficacy in generating rapid onset weight loss, improved glucose regulation and reduced mortality compared with other invasive procedures. VSG is associated with reduced appetite, however, the relative importance of energy expenditure to VSG-induced weight loss and changes in glucose regulation, particularly that in brown adipose tissue (BAT), remains unclear. The aim of this study was to investigate the role of BAT thermogenesis in the efficacy of VSG in a rodent model. MethodsDiet-induced obese male Sprague–Dawley rats were either sham-operated, underwent VSG surgery or were pair-fed to the food consumed by the VSG group. Rats were also implanted with biotelemetry devices between the interscapular lobes of BAT to assess local changes in BAT temperature as a surrogate measure of thermogenic activity. Metabolic parameters including food intake, body weight and changes in body composition were assessed. To further elucidate the contribution of energy expenditure via BAT thermogenesis to VSG-induced weight loss, a separate cohort of chow-fed rats underwent complete excision of the interscapular BAT (iBAT lipectomy) or chemical denervation using 6-hydroxydopamine (6-OHDA). To localize glucose uptake in specific tissues, an oral glucose tolerance test was combined with an intraperitoneal injection of 14C-2-deoxy-d-glucose (14C-2DG). Transneuronal viral tracing was used to identify 1) sensory neurons directed to the stomach or small intestine (H129-RFP) or 2) chains of polysynaptically linked neurons directed to BAT (PRV-GFP) in the same animals. ResultsFollowing VSG, there was a rapid reduction in body weight that was associated with reduced food intake, elevated BAT temperature and improved glucose regulation. Rats that underwent VSG had elevated glucose uptake into BAT compared to sham operated animals as well as elevated gene markers related to increased BAT activity (Ucp1, Dio2, Cpt1b, Cox8b, Ppargc) and markers of increased browning of white fat (Ucp1, Dio2, Cited1, Tbx1, Tnfrs9). Both iBAT lipectomy and 6-OHDA treatment significantly attenuated the impact of VSG on changes in body weight and adiposity in chow-fed animals. In addition, surgical excision of iBAT following VSG significantly reversed VSG-mediated improvements in glucose tolerance, an effect that was independent of circulating insulin levels. Viral tracing studies highlighted a patent neural link between the gut and BAT that included groups of premotor BAT-directed neurons in the dorsal raphe and raphe pallidus. ConclusionsCollectively, these data support a role for BAT in mediating the metabolic sequelae following VSG surgery, particularly the improvement in glucose regulation, and highlight the need to better understand the contribution from this tissue in human patients.

Coconut oil and medium-chain fatty acids attenuate high-fat diet-induced obesity in mice through increased thermogenesis by activating brown adipose tissue.

Coconut oil (CO) and its main ingredients, medium-chain fatty acids (MCFA), present many benefits. Whether MCFA and CO play an equally valuable role in anti-obesity remains unclear. This study compared the anti-obesity effects of CO and MCFA [octanoic acid (C8:0) and decanoic acid (C10:0)] to gain insight into the underlying mechanism. Male C57BL/6J mice were fed either a low-fat diet (LFD) or high-fat diet (100% HFD) replaced with 2.5% MCFA (97.5% HFD + 2.5% MCFA) or 5% CO (95% HFD + 5% CO) for 17 weeks. CO and MCFA ameliorated the HFD-induced abnormal body and adipose depot weights, insulin sensitivity, and energy expenditure (EE), which was associated with brown adipose tissue (BAT) thermogenesis. Furthermore, CO enhanced the expression of thermogenesis markers in BAT, which was consistent with increased BAT activity. CO showed a better effect than MCFA in activating BAT to increase thermogenesis and energy metabolism to combat obesity, which may be attributed to the cooperation of MCFA and other substances in CO. This work provides evidence for the anti-obesity effects of CO, which could be a better alternative to lard in daily diet, rather than pure MCFA.

Impaired mitophagy in Sanfilippo a mice causes hypertriglyceridemia and brown adipose tissue activation

Lysosomal storage diseases result in various developmental and physiological complications, including cachexia. To study the causes for the negative energy balance associated with cachexia, we assessed the impact of sulfamidase deficiency and heparan sulfate storage on energy homeostasis and metabolism in a mouse model of type IIIa mucopolysaccharidosis (MPS IIIa, Sanfilippo A syndrome). At 12-weeks of age, MPS IIIa mice exhibited fasting and postprandial hypertriglyceridemia compared with wildtype mice, with a reduction of white and brown adipose tissues. Partitioning of dietary [3H]triolein showed a marked increase in intestinal uptake and secretion, whereas hepatic production and clearance of triglyceride-rich lipoproteins did not differ from wildtype controls. Uptake of dietary triolein was also elevated in brown adipose tissue (BAT), and notable increases in beige adipose tissue occurred, resulting in hyperthermia, hyperphagia, hyperdipsia, and increased energy expenditure. Furthermore, fasted MPS IIIa mice remained hyperthermic when subjected to low temperature but became cachexic and profoundly hypothermic when treated with a lipolytic inhibitor. We demonstrated that the reliance on increased lipid fueling of BAT was driven by a reduced ability to generate energy from stored lipids within the depot. These alterations arose from impaired autophagosome–lysosome fusion, resulting in increased mitochondria content in beige and BAT. Finally, we show that increased mitochondria content in BAT and postprandial dyslipidemia was partially reversed upon 5-week treatment with recombinant sulfamidase. We hypothesize that increased BAT activity and persistent increases in energy demand in MPS IIIa mice contribute to the negative energy balance observed in patients with MPS IIIa.

Pantothenate protects against obesity via brown adipose tissue activation.

Brown adipose tissue (BAT) is the primary site of adaptive thermogenesis, which is involved in energy expenditure and has received much attention in the field of obesity treatment. By screening a small-molecule compound library of drugs approved by the Food and Drug Administration, pantothenic acid was identified as being able to significantly upregulate the expression of uncoupling protein 1 (UCP1), a key thermogenic protein found in BAT. Pantothenate (PA) treatment decreased adiposity, reversed hepatic steatosis, and improved glucose homeostasis by increasing energy expenditure in C57BL/6J mice fed a high-fat diet. PA also significantly increased BAT activity and induced beige adipocytes formation. Mechanistically, the beneficial effects were mediated by UCP1 because PA treatment was unable to ameliorate obesity in UCP1 knockout mice. In conclusion, we identified PA as an effective BAT activator that can prevent obesity and may represent a promising strategy for the clinical treatment of obesity and related metabolic diseases.NEW & NOTEWORTHY PA treatment effectively and safely protected against obesity via the BAT-UCP1 axis. PA has therapeutic potential for treating obesity and type II diabetes.

The involvement of the adrenergic nervous system in activating human brown adipose tissue and browning.

Obesity is a chronic condition of multifactorial etiology characterized by excessive body fat due to a calorie intake higher than energy expenditure. Given the intrinsic limitations of surgical interventions and the difficulties associated with lifestyle changes, pharmacological manipulation is currently one of the main therapies for metabolic diseases. Approaches aiming to promote energy expenditure through induction of thermogenesis have been explored and, in this context, brown adipose tissue (BAT) activation and browning have been shown to be promising strategies. Although such processes are physiologically stimulated by the sympathetic nervous system, not all situations that are known to increase adrenergic signaling promote a concomitant increase in BAT activation or browning in humans. Thus, a better understanding of factors involved in the thermogenesis attributed to these tissues is needed to enable the development of future therapies against obesity. Herein we carry out a critical review of original articles in humans under conditions previously known to trigger adrenergic responses-namely, cold, catecholamine-secreting tumor (pheochromocytoma and paraganglioma), burn injury, and adrenergic agonists-and discuss which of them are associated with increased BAT activation and browning. BAT is clearly stimulated in individuals exposed to cold or treated with high doses of the β3-adrenergic agonist mirabegron, whereas browning is certainly induced in patients after burn injury or with pheochromocytoma, as well as in individuals treated with β3-adrenergic agonist mirabegron for at least 10weeks. Given the potential effect of increasing energy expenditure, adrenergic stimuli are promising strategies in the treatment of metabolic diseases.

Effect of Liothyronine Treatment on Dermal Temperature and Activation of Brown Adipose Tissue in Female Hypothyroid Patients: A Randomized Crossover Study.

BackgroundThyroid hormones are essential for the full thermogenic response of brown adipose tissue (BAT) and have been implicated in dermal temperature regulation. Nevertheless, persistent cold-intolerance exists among a substantial proportion of hypothyroid patients on adequate levothyroxine (LT4) substitution.Materials and MethodsTo assess if skin temperature and activation of BAT during treatment with liothyronine (LT3) differs from that of LT4 treatment, fifty-nine female hypothyroid patients with residual symptoms on LT4 or LT4/LT3 combination therapy were randomly assigned in a non-blinded crossover study to receive monotherapy with LT4 or LT3 for 12 weeks each. Change in supraclavicular (SCV) skin temperature overlying BAT, and sternal skin temperature not overlying BAT, during rest and cold stimulation were assessed by infrared thermography (IRT). In addition, abundance of exosomal miR-92a, a biomarker of BAT activation, was estimated as a secondary outcome.ResultsCold stimulated skin temperatures decreased less with LT3 vs. LT4 in both SCV (mean 0.009°C/min [95% CI: 0.004, 0.014]; P<0.001) and sternal areas (mean 0.014°C/min [95% CI: 0.008, 0.020]; P<0.001). No difference in serum exosomal miR-92a abundance was observed between the two treatment groupsConclusionLT3 may reduce dermal heat loss. Thermography data suggested increased BAT activation in hypothyroid patients with cold-intolerance. However, this finding was not corroborated by assessment of the microRNA biomarker of BAT activation.Clinical Trial Registration ClinicalTrials.gov, identifier NCT03627611

Lean in one way, in obesity another: effects of moderate exercise in brown adipose tissue of early overfed male Wistar rats.

Early postnatal overfeeding (PO) induces long-term overweight and reduces brown adipose tissue (BAT) thermogenesis. Exercise has been suggested as a possible intervention to increase BAT function. In this study, we investigated chronical effects of moderate-intensity exercise in BAT function in postnatal overfed male Wistar rats METHODS: Litters' delivery was on postnatal-day 0 - PN0. At PN2, litters were adjusted to nine (normal litter - NL) or three pups (small litter - SL) per dam. Animals were weaned on PN21 and in PN30 randomly divided into sedentary (NL-Sed and SL-Sed) or exercised (NL-Exe and SL-Exe), N of 14 litters per group. Exercise protocol started (PN30) with an effort test; training sessions were performed three times weekly at 60% of the VO2max achieved in effort test, until PN80. On PN81, a temperature transponder was implanted beneath the interscapular BAT, whose temperature was assessed in periods of lights-on and -off from PN87 to PN90. Sympathetic nerve activation of BAT was registered at PN90. Animals were euthanized at PN91 and tissues collected RESULTS: PO impaired BAT thermogenesis in lights-on (pPO < 0.0001) and -off (pPO < 0.01). Exercise increased BAT temperature in lights-on (pExe < 0.0001). In NL-Exe, increased BAT activity was associated with higher sympathetic activity (pExe < 0.05), β3-AR (pExe < 0.001), and UCP1 (pExe < 0.001) content. In SL-Exe, increasing BAT thermogenesis is driven by a combination of tissue morphology remodeling (pExe < 0.0001) with greater effect in increasing UCP1 (pExe < 0.001) and increased β3-AR (pExe < 0.001) content. Moderate exercise chronically increased BAT thermogenesis in both, NL and SL groups. In NL-Exe by increasing Sympathetic activity, and in SL-Exe by a combination of increased β3-AR and UCP1 content with morphologic remodeling of BAT. Chronically increasing BAT thermogenesis in obese subjects may lead to higher overall energy expenditure, favoring the reduction of obesity and related comorbidities.

Abstract P496: Exosomes From Brown Adipose Tissue Contain Cardiac Gene-regulatory Elements

Exosomes, extracellular vesicles &lt;150 nm, are vehicles for transporting information (i.e., cargo) allowing tissue to tissue communication. Depending on the cargo, exosomes can have beneficial or detrimental effects. Brown Adipose Tissue (BAT) is a thermogenic organ that modulates metabolism. BAT is also an endocrine organ affecting function of various distant tissue. We have recently shown that BAT is an important modulator of the healthy and diseased heart. Adipose tissue is a large source of circulating exosomes, but the effects of BAT and changing BAT activity on circulating exosome number and cargo are unknown. Identifying the role of BAT in modulating exosome number and cargo is important since the myocardium is highly responsive to exosomes. We used various known approaches that increase BAT activity (cold exposure, BATcold) or decrease BAT activity (BAT removal (BATless), obesity (HFD), aging (old)) and examined the number and content of circulating exosomes. Upon BAT activation via cold exposure, there was a large increase in circulating exosome numbers (see figure). All approaches that results in decreased BAT activity resulted in a decrease in circulating exosome numbers (see figure). We further examined the role of changing BAT activity on the content (i.e., cargo) of the exosomes, specifically focusing on miRNA. Interestingly, changing BAT activity resulted in large changes to the content of the exosomes, with some miRNA increasing levels and other miRNA decreasing levels. Some of these identified miRNA have been shown to exert beneficial effects on the heart and many miRNA having no defined effect on cardiac function. We believe that these BAT activated exosomes have the combination and proportion of circulatory miRNA necessary to enhance and maintain heart function. There is a great need for new strategies and approaches for treatment of cardiovascular disease (CVD). Our data suggest that a novel treatment strategy for CVD can be derived from BAT exosomes.

Melanin-concentrating hormone-producing neurons in the hypothalamus regulate brown adipose tissue and thus contribute to energy expenditure.

Melanin-concentrating hormone (MCH) neuron-ablated mice exhibit increased energy expenditure and reduced fat weight. Increased brown adipose tissue (BAT) activity and locomotor activity-independent energy expenditure contributed to body weight reduction in MCH neuron-ablated mice. MCH neurons send inhibitory input to the medullary raphe nucleus to modulate BAT activity. Hypothalamic melanin-concentrating hormone (MCH) peptide robustly affects energy homeostasis. However, it is unclear whether and how MCH-producing neurons, which contain and release a variety of neuropeptides/transmitters, regulate energy expenditure in the central nervous system and peripheral tissues. We thus examined the regulation of energy expenditure by MCH neurons, focusing on interscapular brown adipose tissue (BAT) activity. MCH neuron-ablated mice exhibited reduced body weight, increased oxygen consumption, and increased BAT activity, which improved locomotor activity-independent energy expenditure. Trans-neuronal retrograde tracing with the recombinant pseudorabies virus revealed that MCH neurons innervate BAT via the sympathetic premotor region in the medullary raphe nucleus (MRN). MRN neurons were activated by MCH neuron ablation. Therefore, endogenous MCH neuron activity negatively modulates energy expenditure via BAT inhibition. MRN neurons might receive inhibitory input from MCH neurons to suppress BAT activity.

Ancestral and developmental cold alter brown adipose tissue function and adult thermal acclimation in Peromyscus.

Small, non-hibernating endotherms increase their thermogenic capacity to survive seasonal cold, through adult phenotypic flexibility. In mammals, this response is primarily driven by remodeling of brown adipose tissue (BAT), which matures postnatally in altricial species. In many regions, ambient temperatures can vary dramatically throughout the breeding season. We used second-generation lab-born Peromyscus leucopus, cold exposed during two critical developmental windows, to test the hypothesis that adult phenotypic flexibility to cold is influenced by rearing temperature. We found that cold exposure during the postnatal period (14°C, birth to 30days) accelerated BAT maturation and permanently remodeled this tissue. As adults, these mice had increased BAT activity and thermogenic capacity relative to controls. However, they also had a blunted acclimation response when subsequently cold exposed as adults (5°C for 6weeks). Mice born to cold-exposed mothers (14°C, entire pregnancy) also showed limited capacity for flexibility as adults, demonstrating that maternal cold stress programs the offspring thermal acclimation response. In contrast, for P. maniculatus adapted to the cold high alpine, BAT maturation rate was unaffected by rearing temperature. However, both postnatal and prenatal cold exposure limited the thermal acclimation response in these cold specialists. Our results suggest a complex interaction between developmental and adult environment, influenced strongly by ancestry, drives thermogenic capacity in the wild.

MiRNA-22 deletion limits white adipose expansion and activates brown fat to attenuate high-fat diet-induced fat mass accumulation

BackgroundObesity, characterized by excessive expansion of white adipose tissue (WAT), is associated with numerous metabolic complications. Conversely, brown adipose tissue (BAT) and beige fat are thermogenic tissues that protect mice against obesity and related metabolic disorders. We recently reported that deletion of miR-22 enhances energy expenditure and attenuates WAT expansion in response to a high-fat diet (HFD). However, the molecular mechanisms involved in these effects mediated by miR-22 loss are unclear. Methods and ResultsHere, we show that miR-22 expression is induced during white, beige, and brown adipocyte differentiation in vitro. Deletion of miR-22 reduced white adipocyte differentiation in vitro. Loss of miR-22 prevented HFD-induced expression of adipogenic/lipogenic markers and adipocyte hypertrophy in murine WAT. In addition, deletion of miR-22 protected mice against HFD-induced mitochondrial dysfunction in WAT and BAT. Loss of miR-22 induced WAT browning. Gain- and loss-of-function studies revealed that miR-22 did not affect brown adipogenesis in vitro. Interestingly, miR-22 KO mice fed a HFD displayed increased expression of genes involved in thermogenesis and adrenergic signaling in BAT when compared to WT mice fed the same diet. ConclusionsCollectively, our findings suggest that loss of miR-22 attenuates fat accumulation in response to a HFD by reducing white adipocyte differentiation and increasing BAT activity, reinforcing miR-22 as a potential therapeutic target for obesity-related disorders.

Short Dietary Intervention with Olive Oil Increases Brown Adipose Tissue Activity in Lean but not Overweight Subjects.

The brown adipose tissue (BAT) is a potential target for the treatment of obesity and metabolic disorders. Its activation by cold exposure or adrenergic drugs can increase systemic insulin sensitivity and improve lipid metabolism; however, little is known about the effects of specific dietary components on BAT activity. We asked if a short-term (4 weeks) dietary intervention with olive oil could modify BAT activity in lean and overweight/obese volunteers. This was a 4-week open clinical trial in which all participants underwent a dietary intervention with extra-virgin olive oil supplementation. As the initial intake of olive oil was controlled all the participants were controls of themselves. The intervention resulted in significant increase in blood monounsaturated fatty acid levels, which was accompanied by increased BAT activity in lean but not in overweight/obese volunteers. In the lean group, an increase in leptin was detected after the intervention, and low leptin values at the beginning of the study were predictive of greater BAT activity after intervention. In addition, increase in leptin concentration was associated with increased BAT activity. Three known endogenous mediators of BAT activity, secretin, fibroblast growth factor 21 (FGF21), and 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) were increased by intervention in lean, whereas only secretin and FGF21 were increased in subjects with excessive weight. This study provides clinical evidence for the impact of monounsaturated fatty acids on BAT activity and an advance in the understanding of the beneficial health effects of olive oil.

Melatonin deficiency decreases brown adipose tissue acute thermogenic capacity of in rats measured by 18F-FDG PET

ObjectiveMelatonin has been shown to increase brown adipose tissue (BAT) mass, which can lead to important metabolic effects, such as bodyweight reduction and glycemic improvement. However, BAT mass can only be measured invasively and. The gold standard for non-invasive measurement of BAT activity is positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-d-glucose (18F-FDG PET). There is no study, to our knowledge, that has evaluated if melatonin influences BAT activity, measured by this imaging technique in animals.MethodsThree experimental groups of Wistar rats (control, pinealectomy, and pinealectomy replaced with melatonin) had an 18F-FDG PET performed at room temperature and after acute cold exposure. The ratio of increased BAT activity after cold exposure/room temperature was called “acute thermogenic capacity” (ATC) We also measured UCP-1 mRNA expression to correlate with the 18F-FDG PET results.ResultsPinealectomy led to reduced acute thermogenic capacity, compared with the other groups, as well as reduced UCP1 mRNA expression.ConclusionMelatonin deficiency impairs BAT response when exposed to acute cold exposure. These results can lead to future studies of the influence of melatonin on BAT, in animals and humans, without needing an invasive evaluation of BAT.

Effects of Nutrition/Diet on Brown Adipose Tissue in Humans: A Systematic Review and Meta-Analysis.

Background: Brown adipose tissue (BAT) provides a minor contribution to diet-induced thermogenesis (DIT)—the metabolic response to food consumption. Increased BAT activity is generally considered beneficial for mammalian metabolism and has been associated with favorable health outcomes. The aim of the current systematic review was to explore whether nutritional factors and/or diet affect human BAT activity. Methods: We searched PubMed Central, Embase and Cochrane Library (trials) to conduct this systematic review (PROSPERO protocol: CRD42018082323). Results: We included 24 eligible papers that studied a total of 2785 participants. We found no mean differences in standardized uptake value of BAT following a single meal or after 6 weeks of L-Arginine supplementation. Resting energy expenditure (REE), however, was increased following a single meal and after supplementation of capsinoid and catechin when compared to a control condition (Z = 2.41, p = 0.02; mean difference = 102.47 (95% CI = 19.28–185.67)). Conclusions: Human BAT activity was not significantly affected by nutrition/diet. Moreover, REE was only increased in response to a single meal, but it is unlikely that this was due to increased BAT activity. BAT activity assessments in response to the chronic effect of food should be considered along with other factors such as body composition and/or environmental temperature.

In Vivo Percutaneous Penetration of Dye into IgWAT and IBAT Using Dissolving Microneedle and Iontophoresis

Abstract Objectives Browning subcutaneous (subQ) white adipose tissue (WAT) or activating brown adipose tissue (BAT) is a promising approach for combating obesity and its comorbidities. Transdermal delivery of browning compounds efficiently to subQ WAT or BAT via microneedle (MN) and iontophoresis, if successful, will represent a new paradigm for treating obesity and its related metabolic disorders in a much more effective, comfortable, easy and safe regimen. The purpose of this study was to investigate the application of dissolving MN in combination with iontophoresis on the skin of mice for transdermal delivery of dye to inguinal WAT (IgWAT) or interscapular BAT (IBAT). Methods Dissolving MN was fabricated using poly (lactic-co-glycolic acid) (PLGA). C57BL/6 J mice received the following 4 treatments: 1. Control (no MN or iontophoresis), 2. MN alone, 3. Iontophoresis alone and 4. MN plus iontophoresis. The 1,1′-dioctadecyl-3,3,3′,3′- tetramethylindodicarbocyanine, 4-chlorobenzenesulfonate salt (DID) dye was loaded into the MN. Treatments were applied on the skin above IgWAT and IBAT of mice. After 24 hours, dye distribution in the body was imaged using an in vivo imaging system (IVIS). After sacrifice, the IgWAT, IBAT, liver, kidneys, lung, and heart were dissected for further analysis. The IVIS imaging system in this study was used to analyze all fluorescence data. Results The average fluorescent intensity from the treated IgWAT and IBAT area of mice was 2.04 102 and 4.16 102 fold higher in MN plus iontophoresis than MN or iontophoresis alone, respectively. The same pattern was also seen in dissected IgWAT and IBAT with 2.73 102 and 3.57 102 fold higher average fluorescent intensity in MN plus iontophoresis treatment than MN or iontophoresis alone. In summary, mice treated with MN plus iontophoresis had higher fluorescent signals in IgWAT and IBAT than the other groups of mice. No fluorescent signals were detected in other collected organs. Conclusions MN in combination with iontophoresis can synergistically enhance transdermal delivery of dye or browning agents to IgWAT and IBAT mice, which might combat obesity via enhancing subQ WAT browning or increasing BAT activity. Funding Sources NIH 1R15AT010395 and AHA 19AIREA34480011.

Elucidation of the roles of brown and brite fat genes: GPR120 is a modulator of brown adipose tissue function.

New Findings What is the topic of this review? Activation of brown adipose tissue with G protein‐coupled receptors as key druggable targets as a strategy to increase energy consumption and reduce fat mass. What advances does it highlight? GPR120 is a fatty acid receptor highly expressed in brown adipose tissue. Its activation by selective ligands increases brown adipose tissue activity. This is mediated by changes in mitochondrial dynamics resulting in increased O2 consumption leading to enhanced nutrient uptake and a reduction in fat mass. The identification of druggable targets to stimulate brown adipose tissue (BAT) is a strategy to combat obesity due to this highly metabolically active tissue utilising thermogenesis to burn fat. Upon cold exposure BAT is activated by the sympathetic nervous system via β3‐adrenergic receptors. Determination of additional receptors expressed by brown, white and brite (brown‐in‐white) fat can lead to new pharmacological treatments to activate BAT. GPR120 is a G protein‐coupled fatty acid receptor that is highly expressed in BAT and further increases in response to cold. Activation of this receptor with the selective agonist TUG‐891 acutely increases fat oxidation and reduces fat mass in mice. The effects are coincident with increased BAT activity and enhanced nutrient uptake. TUG‐891 stimulation of brown adipocytes induces intracellular Ca2+ release which results in elevated O2 consumption as well as mitochondrial depolarisation and fission. Thus, activation of GPR120 in BAT with ligands such as TUG‐891 is a promising strategy to increase fat consumption.

Indirubin, a small molecular deriving from connectivity map (CMAP) screening, ameliorates obesity-induced metabolic dysfunction by enhancing brown adipose thermogenesis and white adipose browning

BackgroundObesity occurs when the body’s energy intake is constantly greater than its energy consumption and the pharmacological enhancing the activity of brown adipose tissue (BAT) and (or) browning of white adipose tissue (WAT) has been considered promising strategies to treat obesity.MethodsIn this study, we took a multi-pronged approach to screen UCP1 activators, including in silico predictions, in vitro assays, as well as in vivo experiments.ResultsBase on Connectivity MAP (CMAP) screening, we obtained multiple drugs that possess a remarkably correlating gene expression pattern to that of enhancing activity in BAT and (or) sWAT signature. Particularly, we focused on a previously unreported drug-indirubin, a compound obtained from the Indigo plant, which is now mainly used for the treatment of chronic myelogenous leukemia (CML). In the current study, our results shown that indirubin could enhance the BAT activity, as evidenced by up-regulated Ucp1 expression and enhanced mitochondrial respiratory function in vitro cellular model. Furthermore, indirubin treatment restrained high-fat diet (HFD)-induced body weight gain, improved glucose homeostasis and ameliorated hepatic steatosis which were associated with the increase of energy expenditure in the mice model. Moreover, we revealed that indirubin treatment increased BAT activity by promoting thermogenesis and mitochondrial biogenesis in BAT and induced browning of subcutaneous inguinal white adipose tissue (sWAT) of mice under HFD. Besides, our results indicated that indirubin induced UCP1 expression in brown adipocytes, at least in part, via activation of PKA and p38MAPK signaling pathways.ConclusionsOur results clearly show that as an effective BAT (as well as beige cells) activator, indirubin may have a protective effect on the prevention and treatment of obesity and its complications.

Brown Adipose Tissue Response to Cold Stimulation Is Reduced in Girls With Autoimmune Hypothyroidism.

ObjectiveThe interaction between thyroid status and brown adipose tissue (BAT) activation is complex. We assessed the effect of autoimmune hypothyroidism (ATD) in female children on BAT activation, measured using infrared thermography.DesignTwenty-six female participants (14 with ATD and 12 healthy controls) between 5 and 17 years of age attended a single study session. Thermal images were taken of the supraclavicular region before, and after, the introduction of a cool stimulus.ResultsParticipants with ATD had lower resting (hypothyroid, 34.9 ± 0.7°C; control, 35.4 ± 0.5°C; P = 0.03) and stimulated (hypothyroid, 35.0 ± 0.6°C; control, 35.5 ± 0.5°C; P = 0.04) supraclavicular temperatures compared with controls, but there was no difference between groups in the temperature increase with stimulation. BAT activation, calculated as the relative temperature change comparing the supraclavicular temperature to a sternal reference region, was reduced in participants with ATD (hypothyroid, 0.1 ± 0.1°C; control, 0.2 ± 0.2°C; P = 0.04). Children with ATD were frequently biochemically euthyroid due to replacement therapy, but, despite this, increased relative supraclavicular temperature was closely associated with increased TSH (r = 0.7, P = 0.01) concentrations.ConclusionsGirls with ATD had an attenuated thermogenic response to cold stimulation compared with healthy controls, but, contrary to expectation, those with suboptimal biochemical control (with higher TSH) showed increased BAT activation. This suggests that the underlying disease process may have a negative effect on BAT response, but high levels of TSH can mitigate, and even stimulate, BAT activity. In summary, thyroid status is a complex determinant of BAT activity in girls with ATD.

Brown adipocytes from induced pluripotent stem cells-how far have we come?

A global increase in the number of individuals who are either overweight or obese is leading to a higher incidence of type 2 diabetes (T2D). Behavioral interventions for the treatment of obesity have yet to deliver desired outcomes, thus introducing a pressing need for molecular- and cellular-based therapies. Excess energy from food is stored in the form of triglycerides in white adipose tissue, which expands during weight gain and can lead to insulin resistance and T2D. By contrast, brown adipose tissue (BAT) releases energy from metabolic substrates in the form of heat and secretes factors that can reverse metabolic disease by acting systemically. Therefore, the ability to increase BAT activity is a promising approach to improve energy balance and metabolic homeostasis. Methods are now being developed to generate brown adipocytes from human induced pluripotent stem cells (hiPSCs), which would (1) provide an unlimited source of cellular material to study human brown adipogenesis, and (2) could be used to develop drug- and cell-based therapies for the treatment of metabolic complications associated with obesity. This article reviews basic BAT biology and details the current progress toward developing brown adipocytes from hiPSCs.