Quantitative Assessment of Morphological Changes in Lipid Droplets and Lipid-Mito Interactions with Aging in Brown Adipose.

The physical characteristics of brown adipose tissue (BAT) are defined by the presence of multilocular lipid droplets (LD) within the brown adipocytes and a high abundance of iron-containing mitochondria, which give it its characteristic color. Normal mitochondrial function is, in part, regulated by organelle-to-organelle contacts. Particularly, the contact sites that mediate mitochondria-LD interactions are thought to have various physiological roles, such as the synthesis and metabolism of lipids. Aging is associated with mitochondrial dysfunction, and previous studies show that there are changes in mitochondrial structure and proteins that modulate organelle contact sites. However, how mitochondria-LD interactions change with aging has yet to be fully clarified. Therefore, we sought to define age-related changes in LD morphology and mitochondria-lipid interactions in BAT. We examined the three-dimensional morphology of mitochondria and LDs in young (3-month) and aged (2-year) murine BAT using serial block face-scanning electron microscopy and the Amira program for segmentation, analysis, and quantification. Analysis showed reductions in LD volume, area, and perimeter in aged samples compared to young samples. Additionally, we observed changes in LD appearance and type in aged samples compared to young samples. Notably, we found differences in mitochondrial interactions with LDs, which could implicate that these contacts may be important for energetics in aging. Upon further investigation, we also found changes in mitochondrial and cristae structure for mitochondria interacting with LD lipids. Overall, these data define the nature of LD morphology and organelle-organelle contacts during aging and provide insight into LD contact site changes that interconnect biogerontology and mitochondrial functionality, metabolism, and bioactivity in aged BAT.

An International Survey Investigating the Incidence and Management of Brown Fat Uptake on 18F-FDG PET/CT at Children's Hospitals and Interventions for Mitigation.

Brown fat can present challenges in patients with cancer who undergo 18F-FDG PET scans. Uptake of 18F-FDG by brown fat can obscure or appear similar to active oncologic lesions, causing clinical challenges in PET interpretation. Small, retrospective studies have reported environmental and pharmacologic interventions for suppressing brown fat uptake on PET; however, there is no clear consensus on best practices. We sought to characterize practice patterns for strategies to mitigate brown fat uptake of 18F-FDG during PET scanning. Methods: A survey was developed and distributed via e-mail LISTSERV to members of the Children's Oncology Group diagnostic imaging committee, the Society for Nuclear Medicine and Molecular Imaging pediatric imaging council, and the Society of Chiefs of Radiology at Children's Hospitals between April 2022 and February 2023. Responses were stored anonymously in REDCap, aggregated, and summarized using descriptive statistics. Results: Fifty-five complete responses were submitted: 51 (93%) faculty and fellow-level physicians, 2 (4%) technologists, and 2 (4%) respondents not reporting their rank. There were 43 unique institutions represented, including 5 (12%) outside the United States. Thirty-eight of 41 (93%) institutions that responded on environmental interventions reported using warm blankets in the infusion and scanning rooms. Less than a third (n = 13, 30%) of institutions reported use of a pharmacologic intervention, with propranolol (n = 5, 38%) being most common, followed by fentanyl (n = 4, 31%), diazepam (n = 2, 15%), and diazepam plus propranolol (n = 2, 15%). Selection criteria for pharmacologic intervention varied, with the most common criterion being brown fat uptake on a prior scan (n = 6, 45%). Conclusion: Clinical practices to mitigate brown fat uptake on pediatric 18F-FDG PET vary widely. Simple environmental interventions including warm blankets or increasing the temperature of the injection and scanning rooms were not universally reported. Less than a third of institutions use pharmacologic agents for brown fat mitigation.

Quantitative assessment of brown adipose tissue whitening in a high-fat-diet murine model using synthetic magnetic resonance imaging.

Purpose: This study aimed to quantitatively evaluate the whitening process of brown adipose tissue (BAT) in mice using synthetic magnetic resonance imaging (SyMRI) and analyzed the correlation between SyMRI quantitative measurements of BAT and serum lipid profiles. Methods: Fifteen C57BL/6 mice were divided into three groups and fed different diets as follows: normal chow diet for 12 weeks, NCD group; high-fat diet (HFD) for 12 weeks, HFD-12w group; and HFD for 36 weeks, HFD-36w group. Mice were scanned using 3.0 T SyMRI. T1 and T2 values of BAT and interscapular BAT (iBAT) volume were measured. After sacrifice, the body weight of mice, lipid profiles, BAT morphology, and uncoupling protein 1 (UCP1) levels were determined. Statistical analysis was performed using one-way analysis of variance or Kruskal-Wallis test followed by Bonferroni correction for pairwise comparisons. Bonferroni-adjusted significance level was set at P < 0.017 (alpha: 0.05/3 = 0.017). Results: T2 values of BAT in the HFD-12w group were significantly higher than those in the NCD group (P < 0.001), and those in the HFD-36w group were significantly higher than those in the other two groups (both P < 0.001). The iBAT volume in the HFD-36w group was significantly higher than that in the HFD-12w (P = 0.013) and NCD groups (P = 0.005). T2 values of BAT and iBAT volume were significantly correlated with serum lipid profiles and mouse body weight. Conclusions: SyMRI can noninvasively evaluate the whitening process of BAT using T2 values and iBAT volume, thereby facilitating the visualization of the whitening process.

Prolonged FGF21 treatment increases energy expenditure and induces weight loss in obese mice independently of UCP1 and adrenergic signaling.

Fibroblast growth factor 21 (FGF21) reduces body weight, which was attributed to induced energy expenditure (EE). Conflicting data have been published on the role of uncoupling protein 1 (UCP1) in this effect. Therefore, we aimed to revisit the thermoregulatory effects of FGF21 and their implications for body weight regulation. We found that an 8-day treatment with FGF21 lowers body weight to similar extent in both wildtype (WT) and UCP1-deficient (KO) mice fed high-fat diet. In WT mice, this effect is solely due to increased EE, associated with a strong activation of UCP1 and with excess heat dissipated through the tail. This thermogenesis takes place in the interscapular region and can be attenuated by a ß-adrenergic inhibitor propranolol. In KO mice, FGF21-induced weight loss correlates with a modest increase in EE, which is independent of adrenergic signaling, and with a reduced energy intake. Interestingly, the gene expression profile of interscapular brown adipose tissue (but not subcutaneous white adipose tissue) of KO mice is massively affected by FGF21, as shown by increased expression of genes encoding triacylglycerol/free fatty acid cycle enzymes. Thus, FGF21 elicits central thermogenic and pyretic effects followed by a concomitant increase in EE and body temperature, respectively. The associated weight loss is strongly dependent on UCP1-based thermogenesis. However, in the absence of UCP1, alternative mechanisms of energy dissipation may contribute, possibly based on futile triacylglycerol/free fatty acid cycling in brown adipose tissue and reduced food intake.

CLCF1 inhibits energy expenditure via suppressing brown fat thermogenesis.

Brown adipose tissue (BAT) is the main site of nonshivering thermogenesis which plays an important role in thermogenesis and energy metabolism. However, the regulatory factors that inhibit BAT activity remain largely unknown. Here, cardiotrophin-like cytokine factor 1 (CLCF1) is identified as a negative regulator of thermogenesis in BAT. Adenovirus-mediated overexpression of CLCF1 in BAT greatly impairs the thermogenic capacity of BAT and reduces the metabolic rate. Consistently, BAT-specific ablation of CLCF1 enhances the BAT function and energy expenditure under both thermoneutral and cold conditions. Mechanistically, adenylate cyclase 3 (ADCY3) is identified as a downstream target of CLCF1 to mediate its role in regulating thermogenesis. Furthermore, CLCF1 is identified to negatively regulate the PERK-ATF4 signaling axis to modulate the transcriptional activity of ADCY3, which activates the PKA substrate phosphorylation. Moreover, CLCF1 deletion in BAT protects the mice against diet-induced obesity by promoting BAT activation and further attenuating impaired glucose and lipid metabolism. Therefore, our results reveal the essential role of CLCF1 in regulating BAT thermogenesis and suggest that inhibiting CLCF1 signaling might be a potential therapeutic strategy for improving obesity-related metabolic disorders.

18F-FDG PET/CT technology for the assessment of brown adipose tissue: an updated review.

INTRODUCTION: This review provides an update of 18 F-fluorodeoxyglucose ([18F] FDG) for Brown adipose tissue (BAT) activity quantification, whose role is not completely understood. AREAS COVERED: We conducted an unstructured search of the literature for any studies employing the [18F] FDG PET in BAT assessment. We explored BAT quantification both in healthy individuals and in different pathologies, after cold exposure and as a metabolic biomarker. The assessment of possible BAT modulators by using [18F] FDG PET is shown. Further PET tracers and novel developments for BAT assessments are also described. EXPERT OPINION: Further PET tracers and imaging modalities are under investigation, but the [18F] FDG PET is currently the method of choice for the evaluation of BAT and further multicentric trials are needed for a better understanding of the BAT physiopathology, also after cold stimuli. The modulation of BAT activity, assessed by [18F] FDG PET imaging, seems a promising tool for the management of conditions such as obesity and type 2 diabetes. Moreover, an interesting possible correlation of BAT activation with prognostic [18F] FDG PET indices in cancer patients should be assessed with further multicentric trials.

Loss of Brain Angiogenesis Inhibitor-3 (BAI3) G-Protein Coupled Receptor in Mice Regulates Adaptive Thermogenesis by Enhancing Energy Expenditure.

Effective energy expenditure is critical for maintaining body weight (BW). However, underlying mechanisms contributing to increased BW remain unknown. We characterized the role of brain angiogenesis inhibitor-3 (BAI3/ADGRB3), an adhesion G-protein coupled receptor (aGPCR), in regulating BW. A CRISPR/Cas9 gene editing approach was utilized to generate a whole-body deletion of the BAI3 gene (BAI3-/-). In both BAI3-/- male and female mice, a significant reduction in BW was observed compared to BAI3+/+ control mice. Quantitative magnetic imaging analysis showed that lean and fat masses were reduced in male and female mice with BAI3 deficiency. Total activity, food intake, energy expenditure (EE), and respiratory exchange ratio (RER) were assessed in mice housed at room temperature using a Comprehensive Lab Animal Monitoring System (CLAMS). While no differences were observed in the activity between the two genotypes in male or female mice, energy expenditure was increased in both sexes with BAI3 deficiency. However, at thermoneutrality (30 °C), no differences in energy expenditure were observed between the two genotypes for either sex, suggesting a role for BAI3 in adaptive thermogenesis. Notably, in male BAI3-/- mice, food intake was reduced, and RER was increased, but these attributes remained unchanged in the female mice upon BAI3 loss. Gene expression analysis showed increased mRNA abundance of thermogenic genes Ucp1, Pgc1α, Prdm16, and Elov3 in brown adipose tissue (BAT). These outcomes suggest that adaptive thermogenesis due to enhanced BAT activity contributes to increased energy expenditure and reduced BW with BAI3 deficiency. Additionally, sex-dependent differences were observed in food intake and RER. These studies identify BAI3 as a novel regulator of BW that can be potentially targeted to improve whole-body energy expenditure.

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

OBJECTIVE: Bariatric 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. METHODS: Diet-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. RESULTS: Following 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. CONCLUSIONS: Collectively, 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.

Assessment of Brown and Beige Adipose Tissue Activation in Mice Using PET/CT Imaging.

In response to cold induction, brown adipose tissues (BAT) and emerged brown-like adipocytes (beige adipocytes) in subcutaneous white adipose tissues (WAT browning/beiging) are activated. Thermogenesis is increased during glucose and fatty acid uptake and metabolism in adult humans and mice. This activation of BAT or WAT beiging to generate heat helps to counteract diet-induced obesity. This protocol applies the glucose analog radiotracer 18F-fluorodeoxyglucose (FDG), coupled with positron emission tomography and computed tomography (PET/CT) scanning to evaluate cold-induced thermogenesis in the active BAT (interscapular region) and browned/beiged WAT (subcutaneous adipose region) in mice. The PET/CT scanning technique not only can quantify cold-induced glucose uptake in well-known BAT and beige-fat depots but also helps to visualize the anatomical location of novel uncharacterized mouse BAT and beige fat where cold-induced glucose uptake is high. Histological analysis is further employed to validate signals of delineated anatomical regions in PET/CT images as bona fide mouse BAT or beiged WAT fat depots.

High Fat Diet Suppresses Energy Expenditure Via Neurons in the Brainstem.

Oxidation of fat by brown adipose tissue (BAT) contributes to energy balance and heat production. During cold exposure, BAT thermogenesis produces heat to warm the body. Obese subjects and rodents, however, show impaired BAT thermogenesis to the cold. Our previous studies suggest that vagal afferents synapsing in the nucleus tractus solitarius (NTS), tonically inhibit BAT thermogenesis to the cold in obese rats. NTS neurons send projections to the dorsal aspect of the lateral parabrachial nucleus (LPBd), which is a major integrative center that receives warm afferent inputs from the periphery and promotes inhibition of BAT thermogenesis. This study investigated the contribution of LPBd neurons in the impairment of BAT thermogenesis in rats fed a high-fat diet (HFD). By using a targeted dual viral vector approach, we found that chemogenetic activation of an NTS-LPB pathway inhibited BAT thermogenesis to the cold. We also found that the number of Fos-labelled neurons in the LPBd was higher in rats fed a HFD than in chow diet-fed rats after exposure to a cold ambient temperature. Nanoinjections of a GABAA receptor agonist into the LPBd area rescued BAT thermogenesis to the cold in HFD rats. These data reveal the LPBd as a critical brain area that tonically suppresses energy expenditure in obesity during skin cooling. These findings reveal novel effects of high-fat diets in the brain and in the control of metabolism and can contribute to the development of therapeutic approaches to regulate fat metabolism.

Astrocytic circadian clock control of energy expenditure by transcriptional stress responses in the ventromedial hypothalamus.

Hypothalamic circuits compute systemic information to control metabolism. Astrocytes residing within the hypothalamus directly sense nutrients and hormones, integrating metabolic information, and modulating neuronal responses. Nevertheless, the role of the astrocytic circadian clock on the control of energy balance remains unclear. We used mice with a targeted ablation of the core-clock gene Bmal1 within Gfap-expressing astrocytes to gain insight on the role played by this transcription factor in astrocytes. While this mutation does not substantially affect the phenotype in mice fed normo-caloric diet, under high-fat diet we unmasked a thermogenic phenotype consisting of increased energy expenditure, and catabolism in brown adipose and overall metabolic improvement consisting of better glycemia control, and body composition. Transcriptomic analysis in the ventromedial hypothalamus revealed an enhanced response to moderate cellular stress, including ER-stress response, unfolded protein response and autophagy. We identified Xbp1 and Atf1 as two key transcription factors enhancing cellular stress responses. Therefore, we unveiled a previously unknown role of the astrocytic circadian clock modulating energy balance through the regulation of cellular stress responses within the VMH.

Inulin increases the beneficial effects of rhubarb supplementation on high-fat high-sugar diet-induced metabolic disorders in mice: impact on energy expenditure, brown adipose tissue activity, and microbiota.

Consumption of prebiotics and plant-based compounds have many beneficial health effects through modulation of gut microbiota composition and are considered as promising nutritional strategy for the treatment of metabolic diseases. In the present study, we assessed the separated and combined effects of inulin and rhubarb on diet-induced metabolic disease in mice. We showed that supplementation with both inulin and rhubarb abolished the total body and fat mass gain upon high-fat and high-sucrose diet (HFHS) as well as several obesity-associated metabolic disorders. These effects were associated with increased energy expenditure, lower whitening of the brown adipose tissue, higher mitochondria activity and increased expression of lipolytic markers in white adipose tissue. Despite modifications of intestinal gut microbiota and bile acid compositions by inulin or rhubarb alone, combination of both inulin and rhubarb had minor additional impact on these parameters. However, the combination of inulin and rhubarb increased the expression of several antimicrobial peptides and higher goblet cell numbers, thereby suggesting a reinforcement of the gut barrier. Together, these results suggest that the combination of inulin and rhubarb in mice potentiates beneficial effects of separated rhubarb and inulin on HFHS-related metabolic disease and could be considered as nutritional strategy for the prevention and treatment of obesity and related pathologies.

Astragalus polysaccharide prevents heart failure-induced cachexia by alleviating excessive adipose expenditure in white and brown adipose tissue.

BACKGROUND: Astragalus polysaccharide (APS) is a key active ingredient isolated from Astragalus membranaceus that has been reported to be a potential treatment for obesity and diabetes by regulating lipid metabolism and adipogenesis, alleviating inflammation, and improving insulin resistance. However, whether APS regulates lipid metabolism in the context of cachexia remains unclear. Therefore, this study analysed the effects of APS on lipid metabolism and adipose expenditure in a heart failure (HF)-induced cardiac cachexia rat model.  METHODS: A salt-sensitive hypertension-induced cardiac cachexia rat model was used in the present study. Cardiac function was detected by echocardiography. The histological features and fat droplets in fat tissue and liver were observed by H&E staining and Oil O Red staining. Immunohistochemical staining, Western blotting and RT‒qPCR were used to detect markers of lipolysis and adipose browning in white adipose tissue (WAT) and thermogenesis in brown adipose tissue (BAT). Additionally, sympathetic nerve activity and inflammation in adipose tissue were detected. RESULTS: Rats with HF exhibited decreased cardiac function and reduced adipose accumulation as well as adipocyte atrophy. In contrast, administration of APS not only improved cardiac function and increased adipose weight but also prevented adipose atrophy and FFA efflux in HF-induced cachexia. Moreover, APS inhibited HF-induced lipolysis and browning of white adipocytes since the expression levels of lipid droplet enzymes, including HSL and perilipin, and beige adipocyte markers, including UCP-1, Cd137 and Zic-1, were suppressed after administration of APS. In BAT, treatment with APS inhibited PKA-p38 MAPK signalling, and these effects were accompanied by decreased thermogenesis reflected by decreased expression of UCP-1, PPAR-γ and PGC-1α and reduced FFA ß-oxidation in mitochondria reflected by decreased Cd36, Fatp-1 and Cpt1. Moreover, sympathetic nerve activity and interleukin-6 levels were abnormally elevated in HF rats, and astragalus polysaccharide could inhibit their activity. CONCLUSION: APS prevented lipolysis and adipose browning in WAT and decreased BAT thermogenesis. These effects may be related to suppressed sympathetic activity and inflammation. This study provides a potential approach to treat HF-induced cardiac cachexia.

A Review of Structural Features, Biological Functions and Biotransformation Studies in Adipose Tissues and an Assessment of Progress and Implications.

Roles for adipose tissues in energy metabolism, health maintenance and disease onset have been established. Evidence indicates that white, brown and beige fats are quite different in terms of their cellular origin and biological characteristics. These differences are significant in targeting adipocytes to study the pathogenesis and prevention strategies of related diseases. The biotransformations of white, brown and beige fat cells constitute an intriguing topic worthy of further study, and the molecular mechanisms underlying the biotransformations of white, brown and beige fat cells remain to be elucidated. Hence, we herein collected evidence from studies on adipose tissue or adipocytes, and we extracted the structural features, biologic functions, and biotransformations of adipose tissue/adipocytes. The present review aimed to summarize the latest research progress and propose novel research directions with respect to adipose tissue and adipocytes. We posit that this work will provide new insights and opportunities in the effective treatment strategies for obesity, diabetes and other lipid-related diseases. It will also contribute to our knowledge of the basic biologic underpinnings of adipocyte biology.

Interventions associated with brown adipose tissue activation and the impact on energy expenditure and weight loss: A systematic review.

Background: Brown adipose tissue (BAT) plays a role in modulating energy expenditure. People with obesity have been shown to have reduced activation of BAT. Agents such as ß-agonists, capsinoids, thyroid hormone, sildenafil, caffeine, or cold exposure may lead to activation of BAT in humans, potentially modulating metabolism to promote weight loss. Methods: We systematically searched electronic databases for clinical trials testing the effect of these agents and cold exposure on energy expenditure/thermogenesis and the extent to which they may impact weight loss in adults. Results: A total of 695 studies from PubMed, Web of Science, and Medline electronic databases were identified. After the removal of duplicates and further evaluation, 47 clinical trials were analyzed. We observed significant heterogeneity in the duration of interventions and the metrics utilized to estimate thermogenesis/energy expenditure. Changes observed in energy expenditure do not correlate with major weight changes with different interventions commonly known to stimulate thermogenesis. Even though cold exposure appears to consistently activate BAT and induce thermogenesis, studies are small, and it appears to be an unlikely sustainable therapy to combat obesity. Most studies were small and potential risks associated with known side effects of some agents such as ß-agonists (tachycardia), sibutramine (hypertension, tachycardia), thyroid hormone (arrhythmias) cannot be fully evaluated from these small trials. Conclusion: Though the impact of BAT activation and associated increases in energy expenditure on clinically meaningful weight loss is a topic of great interest, further data is needed to determine long-term feasibility and efficacy.

Determination of tissue contributions to the circulating lipid pool in cold exposure via systematic assessment of lipid profiles.

Plasma lipid levels are altered in chronic conditions such as type 2 diabetes and cardiovascular disease as well as during acute stresses such as fasting and cold exposure. Advances in MS-based lipidomics have uncovered a complex plasma lipidome of more than 500 lipids that serve functional roles, including as energy substrates and signaling molecules. This plasma lipid pool is maintained through regulation of tissue production, secretion, and uptake. A major challenge in understanding the lipidome complexity is establishing the tissues of origin and uptake for various plasma lipids, which is valuable for determining lipid functions. Using cold exposure as an acute stress, we performed global lipidomics on plasma and in nine tissues that may contribute to the circulating lipid pool. We found that numerous species of plasma acylcarnitines (ACars) and ceramides (Cers) were significantly altered upon cold exposure. Through computational assessment, we identified the liver and brown adipose tissue as major contributors and consumers of circulating ACars, in agreement with our previous work. We further identified the kidney and intestine as novel contributors to the circulating ACar pool and validated these findings with gene expression analysis. Regression analysis also identified that the brown adipose tissue and kidney are interactors with the plasma Cer pool. Taken together, these studies provide an adaptable computational tool to assess tissue contribution to the plasma lipid pool. Our findings have further implications in understanding the function of plasma ACars and Cers, which are elevated in metabolic diseases.

Combined Phyllostachys pubescens and Scutellaria baicalensis Prevent High-Fat Diet-Induced Obesity via Upregulating Thermogenesis and Energy Expenditure by UCP1 in Male C57BL/6J Mice.

This study examined the anti-obesity effects of a Phyllostachys pubescens (leaf) and Scutellaria baicalensis root mixture (BS21), and its underlying mechanisms of action, in high-fat diet (HFD)-induced obese mice. Mice were fed a HFD with BS21 (100, 200, or 400 mg/kg) for 9 weeks. BS21 reduced body weight, white adipose tissue (WAT) and liver weights, liver lipid accumulation, and adipocyte size. Additionally, BS21 reduced serum concentrations of non-esterified fatty acid, triglyceride, glucose, lactate dehydrogenase, low-density lipoprotein cholesterol, total cholesterol, leptin, and insulin growth factor 1, but elevated the adiponectin concentrations. Furthermore, BS21 suppressed the mRNA levels of lipogenesis-related proteins, such as peroxisome proliferator-activated receptor (PPAR) γ, SREBP-1c, C/EBP-α, fatty acid synthase, and leptin, but increased the mRNA gene expression of lipolysis-related proteins, such as PPAR-α, uncoupling protein (UCP) 2, adiponectin, and CPT1b, in WAT. In addition, BS21 increased the cold-stimulated adaptive thermogenesis and UCP1 protein expression with AMPK activation in adipose tissue. Furthermore, BS21 increased the WAT and mRNA expression of energy metabolism-related proteins SIRT1, PGC-1α, and FNDC5/irisin in the quadriceps femoris muscle. These results suggest that BS21 exerts anti-obesity and antihyperlipidemic activities in HFD-induced obese mice by increasing the thermogenesis and energy expenditure, and regulating lipid metabolism. Therefore, BS21 could be useful for preventing and treating obesity and its related metabolic diseases.

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

KEY POINTS: 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. ABSTRACT: 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.

Acute effect of propranolol on resting energy expenditure in hyperthyroid patients.

Objective: Hyperthyroidism is a common endocrine disorder which leads to higher resting energy expenditure (REE). Increased activity of brown adipose tissue (BAT) contributes to elevated REE in hyperthyroid patients. For rapid control of hyperthyroid symptoms, the non-selective ß-blocker propranolol is widely used. While, long-term treatment with propranolol reduces REE it is currently unclear whether it can also acutely diminish REE. Design: In the present prospective interventional trial we investigated the effect of propranolol on REE in hyperthyroid patients. Methods: Nineteen patients with overt primary hyperthyroidism were recruited from the endocrine outpatient clinic. REE was measured by indirect calorimetry before and after an acute dose of 80mg propranolol and during a control period, respectively. Additionally, skin temperature was recorded at eleven predefined locations during each study visit, vital signes and heart rate (HR) were measured before and after administration of propranolol. Results: Mean REE decreased slightly after acute administration of 80mg propranolol (p= 0.03) from 1639 ± 307 kcal/24h to 1594 ± 283 kcal/24h. During the control visit REE did not change significantly. HR correlated significantly with the level of free T3 (R2 = 0.38, p=0.029) free T4 (R2 = 0.39, p=0.026). HR decreased 81 ± 12 bpm to 67 ± 7.6 bpm 90 minutes after oral administration of propranolol (p<0.0001). Skin temperature did not change after propranolol intake. Conclusions: In hyperthyroid patients a single dose of propranolol reduced heart rate substantially but REE diminished only marginally probably due to reduced myocardial energy consumption. Our data speak against a relevant contribution of BAT to the higher REE in hyperthyroidism. Clinical trial registration: ClinicalTrials.gov, identifier (NCT03379181).

Resting Energy Expenditure and Cold-induced Thermogenesis in Patients With Overt Hyperthyroidism.

CONTEXT: Thyroid hormone (TH) is crucial for the adaptation to cold. OBJECTIVE: To evaluate the effect of hyperthyroidism on resting energy expenditure (REE), cold-induced thermogenesis (CIT) and changes in body composition and weight. METHODS: This was a prospective cohort study at the endocrine outpatient clinic of a tertiary referral center. Eighteen patients with overt hyperthyroidism were included. We measured REE during hyperthyroidism, after restoring euthyroid TH levels and after 3 months of normal thyroid function. In 14 of the 18 patients, energy expenditure (EE) was measured before and after a mild cold exposure of 2 hours and CIT was the difference between EEcold and EEwarm. Skin temperatures at 8 positions were recorded during the study visits. Body composition was assessed by dual X-ray absorption. RESULTS: Free thyroxine (fT4) and free triiodothyronine (fT3) decreased significantly over time (fT4, P = .0003; fT3, P = .0001). REE corrected for lean body mass (LBM) decreased from 42 ±â€…6.7 kcal/24 hour/kg LBM in the hyperthyroid to 33 ±â€…4.4 kcal/24 hour/kg LBM (-21%, P < .0001 vs hyperthyroid) in the euthyroid state and 3 months later to 33 ±â€…5.2 kcal/24 hour/kg LBM (-21%, P = .0022 vs hyperthyroid, overall P < .0001). fT4 (P = .0001) and fT3 (P < 0.0001) were predictors of REE. CIT did not change from the hyperthyroid to the euthyroid state (P = .96). Hyperthyroidism led to increased skin temperature at warm ambient conditions but did not alter core body temperature, nor skin temperature after cold exposure. Weight regain and body composition were not influenced by REE and CIT during the hyperthyroid state. CONCLUSION: CIT is not increased in patients with overt hyperthyroidism.