Stimulation Of Brown Adipose Tissue Research Articles

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.

MiR-143 targets SYK to regulate NEFA uptake and contribute to thermogenesis in male mice.

Excessive energy intake is the main cause of obesity, and stimulation of brown adipose tissue (BAT) and white adipose tissue (WAT) thermogenesis has emerged as an attractive tool for anti-obesity. Although miR-143 has been reported to be associated with BAT thermogenesis, its role remains unclear. Here, we found that miR-143 was highest expression in adipose tissue, especially in BAT. During short-term cold exposure or CL316,243 injected, miR-143 was markedly down-regulated in BAT and subcutaneous WAT (scWAT). Moreover, knockout of miR-143 (KO) increases the body temperature of mice upon cold exposure, which may be due to the increased thermogenesis of BAT and scWAT. More importantly, supplement of miR-143 in BAT of KO mice can inhibit the increase of body temperature in KO mice. Mechanistically, spleen tyrosine kinase (SYK) was revealed for the first time as a new target of miR-143, and deletion of miR-143 facilitates fatty acid uptake in BAT. In addition, we found that brown adipocytes can promote fat mobilization of white adipocytes, and miR-143 may participate in this process. Meanwhile, we demonstrate that inactivation of AC9 in BAT inhibits thermogenesis through AC9-PKA-AMPK-CREB-UCP1 signaling pathway. Overall, our results reveal a novel function of miR-143 on thermogenesis, and a new functional link of the BAT and WAT.

MiR-143-null Is against Diet-Induced Obesity by Promoting BAT Thermogenesis and Inhibiting WAT Adipogenesis.

Excessive energy intake is the main cause of obesity, and stimulation of brown adipose tissue (BAT) thermogenesis has emerged as an attractive tool for anti-obesity. Although miR-143 has been reported to promote white adipocyte differentiation, its role in BAT remains unclear. In our study, we found that during HFD-induced obesity, the expression of miR-143 in BAT was significantly reduced, and the expression of miR-143 in WAT first increased and then decreased. Knockout (KO) of miR-143 with CRISPR/Cas9 did not affect the energy metabolism of normal diet fed mice and brown adipocyte differentiation but inhibited the differentiation of white adipocytes. Importantly, during high fat diet-induced obesity, miR-143KO significantly reduced body weight, and improved energy expenditure, insulin sensitivity, and glucose tolerance. Further exploration showed that miR-143KO reduced the weight of adipose tissue, promoted mitochondrial number and functions, induced thermogenesis and lipolysis of BAT, increased lipolysis, and inhibited lipogenesis of white adipose tissue (WAT). Our study considerably improves our collective understanding of the function of miR-143 in adipose tissue and its potential significance in anti-obesity and provides a new avenue for the management of obesity through the inhibition of miR-143 in BAT and WAT.

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

A pyrexic effect of FGF21 independent of energy expenditure and UCP1

ObjectiveAdministration of FGF21 to mice reduces body weight and increases body temperature. The increase in body temperature is generally interpreted as hyperthermia, i.e. a condition secondary to the increase in energy expenditure (heat production). Here, we examine an alternative hypothesis: that FGF21 has a direct pyrexic effect, i.e. FGF21 increases body temperature independently of any effect on energy expenditure. MethodsWe studied the effects of FGF21 treatment on body temperature and energy expenditure in high-fat-diet-fed and chow-fed mice exposed acutely to various ambient temperatures, in high-fat diet-fed mice housed at 30 °C (i.e. at thermoneutrality), and in mice lacking uncoupling protein 1 (UCP1). ResultsIn every model studied, FGF21 increased body temperature, but energy expenditure was increased only in some models. The effect of FGF21 on body temperature was more (not less, as expected in hyperthermia) pronounced at lower ambient temperatures. Effects on body temperature and energy expenditure were temporally distinct (daytime versus nighttime). FGF21 enhanced UCP1 protein content in brown adipose tissue (BAT); there was no measurable UCP1 protein in inguinal brite/beige adipose tissue. FGF21 increased energy expenditure through adrenergic stimulation of BAT. In mice lacking UCP1, FGF21 did not increase energy expenditure but increased body temperature by reducing heat loss, e.g. a reduced tail surface temperature. ConclusionThe effect of FGF21 on body temperature is independent of UCP1 and can be achieved in the absence of any change in energy expenditure. Since elevated body temperature is a primary effect of FGF21 and can be achieved without increasing energy expenditure, only limited body weight-lowering effects of FGF21 may be expected.

Repurposing beta-3 adrenergic receptor agonists for Alzheimer\u2019s disease: beneficial effects in a mouse model

BackgroundOld age, the most important risk factor for Alzheimer’s disease (AD), is associated with thermoregulatory deficits. Brown adipose tissue (BAT) is the main thermogenic driver in mammals and its stimulation, through β3 adrenergic receptor (β3AR) agonists or cold acclimation, counteracts metabolic deficits in rodents and humans. Studies in animal models show that AD neuropathology leads to thermoregulatory deficits, and cold-induced tau hyperphosphorylation is prevented by BAT stimulation through cold acclimation. Since metabolic disorders and AD share strong pathogenic links, we hypothesized that BAT stimulation through a β3AR agonist could exert benefits in AD as well.MethodsCL-316,243, a specific β3AR agonist, was administered to the triple transgenic mouse model of AD (3xTg-AD) and non-transgenic controls from 15 to 16 months of age at a dose of 1 mg/kg/day i.p.ResultsHere, we show that β3AR agonist administration decreased body weight and improved peripheral glucose metabolism and BAT thermogenesis in both non-transgenic and 3xTg-AD mice. One-month treatment with a β3AR agonist increased recognition index by 19% in 16-month-old 3xTg-AD mice compared to pre-treatment (14-month-old). Locomotion, anxiety, and tau pathology were not modified. Finally, insoluble Aβ42/Aβ40 ratio was decreased by 27% in the hippocampus of CL-316,243-injected 3xTg-AD mice.ConclusionsOverall, our results indicate that β3AR stimulation reverses memory deficits and shifts downward the insoluble Aβ42/Aβ40 ratio in 16-month-old 3xTg-AD mice. As β3AR agonists are being clinically developed for metabolic disorders, repurposing them in AD could be a valuable therapeutic strategy.

Thyroid hormones in the regulation of brown adipose tissue thermogenesis.

A normal thyroid status is crucial for body temperature homeostasis, as thyroid hormone regulates both heat loss and conservation as well as heat production in the thermogenic tissues. Brown adipose tissue (BAT) is the major site of non-shivering thermogenesis and an important target of thyroid hormone action. Thyroid hormone not only regulates the tissue’s sensitivity to sympathetic stimulation by norepinephrine but also the expression of uncoupling protein 1, the key driver of BAT thermogenesis. Vice versa, sympathetic stimulation of BAT triggers the expression of deiodinase type II, an enzyme that enhances local thyroid hormone availability and signaling. This review summarizes the current knowledge on how thyroid hormone controls BAT thermogenesis, aiming to dissect the direct actions of the hormone in BAT and its indirect actions via the CNS, browning of white adipose tissue or heat loss over body surfaces. Of particular relevance is the apparent dose dependency of the observed effects, as we find that minor or moderate changes in thyroid hormone levels often have different effects as compared to high pharmacological doses. Moreover, we conclude that the more recent findings require a reevaluation of older studies, as key aspects such as heat loss or central BAT activation may not have received the necessary attention during the interpretation of these early findings. Finally, we provide a list of what we believe are the most relevant questions in the field that to date are still enigmatic and require further studies.

Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation

Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting the β3-adrenergic receptor (β3-AR), the adrenergic receptor believed to mediate BAT thermogenesis, have historically performed poorly in human clinical trials. Here we report that, in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of β3-AR. Oral administration of the β3-AR agonist mirabegron only elicited increases in BAT thermogenesis when ingested at the maximal allowable dose. This led to off-target binding to β1-AR and β2-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. ADRB2 was co-expressed with UCP1 in human brown adipocytes. Pharmacological stimulation and inhibition of the β2-AR as well as knockdown of ADRB1, ADRB2, or ADRB3 in human brown adipocytes all confirmed that BAT lipolysis and thermogenesis occur through β2-AR signaling in humans (ClinicalTrials.govNCT02811289).

NCLX prevents cell death during adrenergic activation of the brown adipose tissue

A sharp increase in mitochondrial Ca2+ marks the activation of brown adipose tissue (BAT) thermogenesis, yet the mechanisms preventing Ca2+ deleterious effects are poorly understood. Here, we show that adrenergic stimulation of BAT activates a PKA-dependent mitochondrial Ca2+ extrusion via the mitochondrial Na+/Ca2+ exchanger, NCLX. Adrenergic stimulation of NCLX-null brown adipocytes (BA) induces a profound mitochondrial Ca2+ overload and impaired uncoupled respiration. Core body temperature, PET imaging of glucose uptake and VO2 measurements confirm a thermogenic defect in NCLX-null mice. We show that Ca2+ overload induced by adrenergic stimulation of NCLX-null BAT, triggers the mitochondrial permeability transition pore (mPTP) opening, leading to a remarkable mitochondrial swelling and cell death. Treatment with mPTP inhibitors rescue mitochondrial function and thermogenesis in NCLX-null BAT, while calcium overload persists. Our findings identify a key pathway through which BA evade apoptosis during adrenergic stimulation of uncoupling. NCLX deletion transforms the adrenergic pathway responsible for thermogenesis activation into a death pathway.

The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation

During β-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1α. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activation of the Ucp1 enhancer and Pgc-1α promoter. P62Δ69-251 mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1α expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62Δ69-251 mice, global p62−/− and Ucp1-Cre p62flx/flx mice. BAT dysfunction resulting from p62 deficiency is manifest after birth and obesity subsequently develops despite normal food intake, intestinal nutrient absorption and locomotor activity. In summary, our data identify p62 as a master regulator of BAT function in that it controls the Ucp1 pathway through regulation of ATF2 genomic binding.

SAT-653 Exploring the Role of Brown Adipokines on Hepatic Insulin Resistance Using a Microfluidic Organ-On-Chip

The development of insulin resistance (IR) in liver is a key of pathophysiologic response in type 2 diabetes. Although insulin resistance impairs its ability to suppress hepatic glucose production, insulin regulation of lipogenesis is maintained (1). Currently available insulin sensitizers are effective at lowering glucose levels, but have significant adverse effect on weight gain due to triglyceride accumulation, which highlights a need to develop new therapeutic treatment options for type 2 diabetes. Brown adipose tissue (BAT) has been studied as a new target for anti-obesity and type 2 diabetes as BAT stimulation increases energy expenditure, reduces adiposity, and improves insulin sensitivity (2). However, the underlying mechanisms are not completely understood. To identify the role of BAT adipokines on hepatic insulin resistance, we developed an insulin resistant liver organ-on-chip model and then perfused primary mouse brown adipocyte conditioned media through the hepatocytes. Our results demonstrate that IR hepatocytes treated with brown adipocyte - conditioned media restores insulin sensitivity and improves glucose metabolism. This was verified by significantly increased expression of Phospho-Akt (Ser473) and glucose production gene markers (G6pc and PEPCK), lowered glucose production, increased glucose uptake, and increased glycogen synthesis in treated hepatocytes over IR group (p < 0.05). Our results also indicate that brown adipocyte - conditioned media treatment has the potential to suppress lipogenesis in hepatic insulin resistance. This was confirmed by significantly reduced expression of a lipogenesis gene marker (SREPB1) and fatty acid uptake in treated hepatocytes over IR group (p < 0.05). Current efforts are focused towards identifying the BAT adipokine via mass spectrometry. We conclude that BAT-derived endocrine factors could be a potential target for new drug discovery for obesity and type 2 diabetes treatment. Reference: (1) Langlet et al. Cell. 2017 Nov;171(4):824-835. (2) Subhadraw et al. Am J Physiol Endocrinol Metlab. 2015 Jun;308(12):E1043-E1055. Nothing to Disclose: NT, CL, AT, FZ, KK, JM, RC, AB

Is Exercise a Match for Cold Exposure? Common Molecular Framework for Adipose Tissue Browning.

Exercise is commonly utilized for weight loss, yet research has focused less on specific modifications to adipose tissue metabolism. White adipose tissue (WAT) is the storage form of fat, whereas brown adipose tissue (BAT) is a thermogenic tissue whose uncoupling increases energy expenditure. The most established BAT activator is cold exposure, which also transforms WAT into "beige cells" that express uncoupling protein 1 (UCP1). Preliminary evidence in rodents suggests exercise elicits similar effects. The purpose of this review is to parallel and examine differences between exercise and cold exposure on BAT activation and beige induction. Like cold exposure, exercise stimulates the sympathetic nervous system and activates molecular pathways responsible for BAT/beige activation, including upregulation of BAT activation markers (UCP1, proliferator-activated receptor-gamma coactivator-1α) and stimulation of endocrine activators (fibroblast growth factor-21, irisin, and natriuretic peptides). Further, certain BAT activators are altered exclusively by exercise (interleukin-6, lactate). Markers of BAT activation increase from both cold exposure and exercise, whereas effects in WAT are compartment-specific. Stimulation of endocrine activators depends on numerous factors, including stimulus intensity and duration. Evidence of these analogous, albeit not mirrored, mechanisms is demonstrated by increases in adipose activity in rodents, while effects remain challenging to quantify in humans.

NMR and Mass Spectroscopy Based Comparison of Blood Metabolites from Dantrolene and SR59230A Treated Arctic Ground Squirrels

Arctic ground squirrels (AGS) hibernate during winter, undergoing cycles of torpor, where body temperatures plummet as low as −3°C followed by rapid rewarming to 37°C during interbout arousals (IBA). While IBAs only occur in certain species that experience torpor, they offer a unique model into which one can observe the specific mechanisms responsible for thermogenesis. Rapid rewarming at IBA onset increases AGS body temperature above 15°C through the activation of brown adipose tissue (BAT). Above 15°C, shivering thermogenesis is able to contribute to warming back up to original body temperature. However, the relative contributions of these two thermogenic processes during IBA is not well understood. AGS were treated across periods of coupled torpor cycles, whereby during the second cycle AGS were treated with either carrier (control) or a selected inhibitor. BAT inhibition using SR59230A, a β3‐adrenergic receptor inhibitor, would be expected to strain the rapid heat production. Shivering thermogenesis utilizes calcium cycling and the Ryanodine receptor in skeletal muscles; the use of dantrolene reduces the thermogenic mechanism needed to reach 37°, effectively inhibiting the Ryanodine receptor in muscle. Relative concentrations of blood plasma metabolites were quantified using nuclear magnetic resonance (NMR) to compare whole and polar extracted plasma. The NMR method was compared against full metabolomic analysis performed using liquid chromatography tandem mass spectroscopy (LC MS‐MS). NMR analysis resulted in higher peak resolution quality and increased metabolite identification in polar and lipid extraction samples compared to whole samples, whereas LC MS‐MS provided a greater abundance of metabolites. Overall, total metabolites were significantly reduced during hibernation. Dantrolene treated AGS had alterations in metabolites indicative of increased energy demand. Furthermore, SR treatment resulted in profiles describing decreased beta‐oxidation and generally lower total metabolites compared to Dantrolene. These trends indicate that changes in calcium cycling and BAT stimulation during hibernation can have profound effects on the animals ability to efficiently balance energy usage.Support or Funding InformationResearch reported in this publication was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103395. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the NIH. BLaST is supported by the NIH with the linked awards; TL4GM118992, RL5GM118990, UL1GM118991.

Hypothyroidism and obesity: Is there a bidirectional link? What is the impact on our clinical practice?

It is well established that hypothyroidism causes weight gain, but novel emerging data suggest that obesity may actually lead to hypothyroidism. The interplay between leptin, thyroid hormones (THs), and thyroid autoimmunity in obese patients needs special attention. Clinicians need to be more cautious while interpreting elevated thyroid-stimulating hormone levels in obese individuals to avoid inappropriate labeling of hypothyroidism and unjustified use of TH therapy. It would seem reasonable to measure circulating plasma levels of THs and thyroid autoantibodies in these individuals. Stimulation of brown adipose tissue in adults, specifically through TH-mediated pathways, may seem a promising therapeutic target for obesity; however, the evidence has been inconclusive regarding effectiveness of TH therapy in treating obesity. Moreover, the effect of weight loss on thyroid function has been variable as per different studies. We aim to review the available evidence regarding the possible bidirectional link between hypothyroidism and obesity, explore responsible underlying mechanisms, and discuss the impact of this knowledge on our clinical practice.

Human BAT Thermogenesis is Stimulated by the β &lt;sub&gt;2&lt;/sub&gt;-Adrenergic Receptor

Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting the β3-adrenergic receptor (β3-AR), the adrenergic receptor believed to mediate BAT thermogenesis, have historically performed poorly in human clinical trials. Here we report that, in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of the β3-AR but rather driven primarily through the β2-AR. Oral administration of the β3-AR agonist mirabegron only elicited increases in BAT thermogenesis when ingested at the maximal allowable dose. Such a dose led to off-target binding to the β1-AR and β2-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. In vitro pharmacological stimulation as well as pharmacological and genetic inhibition of the β2-AR in human primary brown adipocytes all confirmed that this β-AR subtype is essential to simulate BAT lipolysis and thermogenesis in humans (ClinicalTrials.gov NCT02811289).

Repeated cold exposures protect a mouse model of Alzheimer's disease against cold-induced tau phosphorylation

ObjectiveOld age is associated with a rise in the incidence of Alzheimer's disease (AD) but also with thermoregulatory deficits. Indicative of a link between the two, hypothermia induces tau hyperphosphorylation. The 3xTg-AD mouse model not only develops tau and amyloid pathologies in the brain but also metabolic and thermoregulatory deficits. Brown adipose tissue (BAT) is the main thermogenic driver in mammals, and its stimulation counteracts metabolic deficits in rodents and humans. We thus investigated whether BAT stimulation impedes AD neuropathology. Methods15-month-old 3xTg-AD mice were subjected to repeated short cold exposures (RSCE), consisting of 4-hour sessions of cold exposure (4 °C), five times per week for four weeks, compared to animals kept at housing temperature. ResultsFirst, we confirmed that 3xTg-AD RSCE-trained mice exhibited BAT thermogenesis and improved glucose tolerance. RSCE-trained mice were completely resistant to tau hyperphosphorylation in the hippocampus induced by a 24-hour cold challenge. Finally, RSCE increased plasma levels of fibroblast growth factor 21 (FGF21), a batokine, which inversely correlated with hippocampal tau phosphorylation. ConclusionsOverall, BAT stimulation through RSCE improved metabolic deficits and completely blocked cold-induced tau hyperphosphorylation in the 3xTg-AD mouse model of AD neuropathology. These results suggest that improving thermogenesis could exert a therapeutic effect in AD.

Activation of brown adipose tissue enhances the efficacy of caloric restriction for treatment of nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is the form of nonalcoholic fatty liver disease that can evolve into cirrhosis. Lifestyle modifications achieving 10% weight loss reverse NASH, but there are no effective approved drug treatments. We previously identified defective adaptive thermogenesis as a factor contributing to metabolic syndrome and hepatic steatosis. We have now tested whether increasing nonshivering thermogenesis can improve preexisting NASH in mice. In high-fat diet-fed foz/foz mice with established NASH, treatment with β3AR agonist restored brown adipose tissue (BAT) function, decreased body weight, improved glucose tolerance, and reduced hepatic lipid content compared to untreated counterparts, but had no impact on liver inflammation or on nonalcoholic fatty liver disease activity score (NAS). Similarly, β3AR agonist did not alter liver pathology in other steatohepatitis models, including MCD diet-fed diabetic obese db/db mice. Caloric restriction alone alleviated the hepatic inflammatory signature in foz/foz mice. Addition of a β3AR agonist to mice subjected to caloric restriction enhanced weight loss and glucose tolerance, and improved liver steatosis, hepatocellular injury, and further reduced liver inflammation. These changes contributed to a significantly lower NAS score such as no (0/9) animals in this group fulfilled the criteria for NASH pathology compared to eight out of ten mice under caloric restriction alone. In conclusion, β3AR agonist counteracts features of the metabolic syndrome and alleviates steatosis, but does not reverse NASH. However, when coupled with weight loss therapy, BAT stimulation provides additional therapeutic advantages and reverses NASH.Defective thermogenic response to calorie overload contributes to obesity and, in foz/foz mice, to nonalcoholic steatohepatitis (NASH). Activation of brown adipose tissue function by b3AR-agonists together with moderate calorie restriction improves the obese phenotype and resolves NASH pathology. This identifies the brown adipose tissue as a target for adjuvant therapy for NASH.

Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes

Pharmacological stimulation of brown adipose tissue (BAT) thermogenesis to increase energy expenditure is progressively being pursued as a viable anti-obesity strategy. Here, we report that pharmacological activation of the cold receptor transient receptor potential cation channel subfamily M member 8 (TRPM8) with agonist icilin mimics the metabolic benefits of cold exposure. In diet-induced obese (DIO) mice, treatment with icilin enhances energy expenditure, and decreases body weight, without affecting food intake. To further potentiate the thermogenic action profile of icilin and add complementary anorexigenic mechanisms, we set out to identify pharmacological partners next to icilin. To that end, we specifically targeted nicotinic acetylcholine receptor (nAChR) subtype alpha3beta4 (α3β4), which we had recognized as a potential regulator of energy homeostasis and glucose metabolism. Combinatorial targeting of TRPM8 and nAChR α3β4 by icilin and dimethylphenylpiperazinium (DMPP) orchestrates synergistic anorexic and thermogenic pathways to reverse diet-induced obesity, dyslipidemia, and glucose intolerance in DIO mice.

Physiological Responses to Daily Use of Beta-Three Adrenergic Receptor Agonist, Mirabegron

Background: Brown Adipose Tissue (BAT) in adult humans has become increasingly recognized to contribute to energy consumption and modulate metabolism. To date, BAT stimulation has predominately relied on cold exposure. However, long-term cold exposure is impractical as a treatment option for obesity and diabetes. Thus, we investigated if a chronic pharmacotherapeutic approach could stimulate BAT and contribute to metabolic health. Methods: In an ongoing study, 6 healthy female volunteers received 4 weeks of daily mirabegron (Myrbetriq, Astellas Pharma) 100 mg, a β3 adrenergic receptor (AR) agonist. Acute responses were determined by comparing effects before and then five hours after dosing. Chronic changes were assessed after 4 weeks of treatment. The primary endpoint was the change in BAT metabolic activity measured by 18F-FDG PET/CT. Secondary endpoints included resting energy expenditure (REE), insulin and glucose sensitivity, liver steatosis, and cardiovascular stimulation. Results: Acute effects of mirabegron included consistent increases in rate pressure product (RPP), REE, and serum non-esterified fatty acids (NEFA) (p&amp;lt;0.05, p=0.06, p&amp;lt;.05). After 4 weeks, there was a wide range of changes in BAT volume (41 ± 223 mL, p=0.86). Body weight was unchanged (0.3 ± 0.62 kg). Several physiological responses after chronic treatment were blunted, including smaller mirabegron-induced increases in RPP, NEFA, and REE. Yet, there were significant increases in sleeping EE (72 ± 23 kcal/d, p=0.03), insulin sensitivity (1.5 ± .6 (mU/L*min, p=0.05), and liver steatosis (30 ± 10 dB/m, p = 0.04) after 4 weeks. Conclusions: Acute treatment with mirabegron in women successfully activates BAT thermogenesis. Preliminary data show chronic treatment resulted in a blunting of several responses, consistent with physiological attenuation of β-AR signaling. The increases in sleeping EE and improved insulin sensitivity suggest chronic mirabegron treatment may help alleviate metabolic disease. Disclosure A. O'Mara: None. A. Cypess: None. C. Cero: None. J.W. Johnson: None. J.D. Linderman: None. B. Leitner: None. L. Fletcher: None. R. Brychta: None. D. Kapuria: None. S. McGehee: None. Y. Rotman: None.

Stimulation of the ß3-Adrenergic Receptor via Mirabegron Induces Lipolysis and Thermogenesis in Human Adipocytes

In rodent models, the β3-adrenergic receptor (AR) is responsible for thermogenesis in brown adipose tissue (BAT) and lipolysis in white adipose tissue (WAT). In contrast, the contribution of β3-AR in human adipocytes is controversial due to the low expression of the β3-AR in WAT and access only to partial β3-AR agonists. Mirabegron, an FDA-approved drug for overreactive bladder, is a selective human β3-AR agonist. In a recent clinical trial, mirabegron activated human BAT thermogenesis and WAT lipolysis. Therefore, we investigated the distribution and relative contribution of β1/2/3-AR in (i) whole white (hWAT) and brown (hBAT) adipose tissue from human autopsies and (ii) immortalized human white (hWA) and brown (hBA) adipocytes. Among the three β-ARs, β1-AR and β2-AR are similarly expressed in brown and white adipose tissue, whereas β3-AR has the highest expression in hBAT. In immortalized differentiated cells, hBA have a significantly higher expression of β3-AR compared to hWA. To assess the functionally of these receptors in adipocytes, dose-response curves of agonist-stimulated lipolysis were investigated in differentiated human and mouse adipocytes. We observed that stimulation of any one of the three β-ARs in human adipocytes induces a significant increase in glycerol release, a lipolytic byproduct. However, the effective dose of mirabegron to activate β3-AR-mediated lipolysis in white and brown adipocytes via mirabegron was significantly lower (hWA: EC50 2.55E-09; hBA: EC50 6.31E-09) compared to specific activators of β1-AR or β2-AR. In summary, we identify a major role played by the β3-AR in the regulation of human BAT thermogenesis and WAT lipolysis, both in vivo and in vitro. Due to the comparatively minimal effects of mirabegron treatment on the cardiovascular system, selective β3-AR agonists may be the optimal choice for targeted stimulation of human WAT and BAT. Disclosure C. Cero: None. A. O'Mara: None. J.W. Johnson: None. A.S. Baskin: None. J.D. Linderman: None. A. Cypess: None.