Involution of brown adipose tissue through a Syntaxin 4 dependent pyroptosis pathway.

Aging, chronic high-fat diet feeding, or housing at thermoneutrality induces brown adipose tissue (BAT) involution, a process characterized by reduction of BAT mass and function with increased lipid droplet size. Single nuclei RNA sequencing of aged mice identifies a specific brown adipocyte population of Ucp1-low cells that are pyroptotic and display a reduction in the longevity gene syntaxin 4 (Stx4a). Similar to aged brown adipocytes, Ucp1-STX4KO mice display loss of brown adipose tissue mass and thermogenic dysfunction concomitant with increased pyroptosis. Restoration of STX4 expression or suppression of pyroptosis activation protects against the decline in both mass and thermogenic activity in the aged and Ucp1-STX4KO mice. Mechanistically, STX4 deficiency reduces oxidative phosphorylation, glucose uptake, and glycolysis leading to reduced ATP levels, a known triggering signal for pyroptosis. Together, these data demonstrate an understanding of rapid brown adipocyte involution and that physiologic aging and thermogenic dysfunction result from pyroptotic signaling activation.

Highland deer mice support increased thermogenesis in response to chronic cold hypoxia by shifting uptake of circulating fatty acids from muscles to brown adipose tissue.

During maximal cold challenge (cold-induced V̇O2,max) in hypoxia, highland deer mice (Peromyscus maniculatus) show higher rates of circulatory fatty acid delivery compared with lowland deer mice. Fatty acid delivery also increases with acclimation to cold hypoxia (CH) and probably plays a major role in supporting the high rates of thermogenesis observed in highland deer mice. However, it is unknown which tissues take up these fatty acids and their relative contribution to thermogenesis. The goal of this study was to determine the uptake of circulating fatty acids into 24 different tissues during hypoxic cold-induced V̇O2,max, by using [1-14C]2-bromopalmitic acid. To uncover evolved and environment-induced changes in fatty acid uptake, we compared lab-born and -raised highland and lowland deer mice, acclimated to either thermoneutral (30°C, 21 kPa O2) or CH (5°C, 12 kPa O2) conditions. During hypoxic cold-induced V̇O2,max, CH-acclimated highlanders decreased muscle fatty acid uptake and increased uptake into brown adipose tissue (BAT) relative to thermoneutral highlanders, a response that was absent in lowlanders. CH acclimation was also associated with increased activities of enzymes citrate synthase and ß-hydroxyacyl-CoA dehydrogenase in the BAT of highlanders, and higher levels of fatty acid translocase CD36 (FAT/CD36) in both populations. This is the first study to show that cold-induced fatty acid uptake is distributed across a wide range of tissues. Highland deer mice show plasticity in this fatty acid distribution in response to chronic cold hypoxia, and combined with higher rates of tissue delivery, this contributes to their survival in the cold high alpine environment.

Heat production during exercise in pregnancy: discerning the contribution of total body weight.

Studies have reported enhanced thermoregulatory function as pregnancy progresses; however, it is unclear if differences in thermoregulation are attributed to weight gain or other physiological changes. This study aimed to determine if total body weight will influence thermoregulation (heat production (Hprod)), heart rate, and perceptual measurements in response to weight-bearing exercise during early to late pregnancy. A cross-sectional design of healthy pregnant women at different pregnancy time points (early, T1; middle, T2; late, T3) performed a 7-stage weight-bearing incremental exercise protocol. Measurements of Hprod, HR, and RPE were examined. Two experimental groups were studied: (1) weight matched and (2) non-weight matched, in T1, T2, and T3. During exercise, equivalent Hprod at T1 (326 ± 88 kJ), T2 (330 ± 43 kJ), and T3 (352 ± 52 kJ) (p = 0.504); HR (p = 0.830); and RPE (p = 0.195) were observed in the WM group at each time point. In the NWM group, Hprod (from stages 1-6 of the exercise) increased across pregnancy time points, T1 (291 ± 76 kJ) to T2 (347 ± 41 kJ) and T3 (385 ± 47 kJ) (p < 0.001). HR increased from T1 to T3 in the warm-up to stage 6 (p = 0.009). RPE did not change as pregnancy time point progressed (p = 0.309). Total body weight, irrespective of pregnancy time point, modulates Hprod and HR during exercise. Therefore, accounting for total body weight is crucial when comparing thermoregulatory function during exercise across pregnancy.

Energy expenditure and dietary intake in professional female football players in the Dutch Women's League: Implications for nutritional counselling.

In contrast to male football players, research on the nutritional requirements of female football players is limited. This study aimed to assess total daily energy expenditure (TDEE) in professional female football players, along with body composition, physical activity and dietary intake. This observational study included 15 professional football players playing in the highest Dutch Women's League. TDEE was assessed by doubly labelled water over 14 days, along with resting metabolic rate (RMR; ventilated hood), fat-free mass (FFM; dual-energy x-ray absorptiometry), and dietary intake (24-h recalls). Physical activity energy expenditure (PAEE) was derived from subtracting RMR and estimated diet-induced thermogenesis (10%) from TDEE. TDEE was 2882 ± 278 kcal/day (58 ± 5 kcal/kg FFM) and significantly (p < 0.05) correlated with FFM (r = 0.62). PAEE was 1207 ± 213 kcal/d. Weighted energy intake was 2344 kcal [2023-2589]. Carbohydrate intakes were 3.2 ± 0.7, 4.4 ± 1.1 and 5.3 ± 1.9 g/kg body mass for rest, training and match days, respectively, while weighted mean protein intake was 1.9 ± 0.4 g/kg body mass. In conclusion, the energy requirements of professional female football players are moderate to high and can be explained by the substantial PAEE. To fuel these requirements, sports nutritionists should consider shifting the players' focus towards prioritizing adequate carbohydrate intakes, rather than emphasizing high protein consumption.

Effect of Electroacupuncture Stimulation on Brown Adipose Tissue Thermogenesis.

Background: : 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. Objectives: : 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). Methods: : 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. Results: : 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. Conclusion: : 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.

Wiring the Brain for Wellness: Sensory Integration in Feeding and Thermogenesis: A Report on Research Supported by Pathway to Stop Diabetes.

The recognition of sensory signals from within the body (interoceptive) and from the external environment (exteroceptive), along with the integration of these cues by the central nervous system, plays a crucial role in maintaining metabolic balance. This orchestration is vital for regulating processes related to both food intake and energy expenditure. Animal model studies indicate that manipulating specific populations of neurons in the central nervous system which influence these processes can effectively modify energy balance. This body of work presents an opportunity for the development of innovative weight loss therapies for the treatment of obesity and type 2 diabetes. In this overview, we delve into the sensory cues and the neuronal populations responsible for their integration, exploring their potential in the development of weight loss treatments for obesity and type 2 diabetes. This article is the first in a series of Perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program.

Role of Spexin in White Adipose Tissue Thermogenesis under Basal and Cold-Stimulated Conditions.

Spexin (SPX) is a novel adipokine that plays an emerging role in metabolic diseases due to its involvement in carbohydrate homeostasis, weight loss, appetite control, and gastrointestinal movement, among others. In obese patients, SPX plasma levels are reduced. Little is known about the relationship between SPX and white adipose tissue (WAT) thermogenesis. Therefore, the aim of the present study was to evaluate the role of SPX in this process. C57BL/6J male mice were treated or not with SPX for ten days. On day 3, mice were randomly divided into two groups: one kept at room temperature and the other kept at cold temperature (4 °C). Caloric intake and body weight were recorded daily. At the end of the protocol, plasma, abdominal (epididymal), subcutaneous (inguinal), and brown AT (EAT, IAT, and BAT, respectively) depots were collected for measurements. We found that SPX treatment reduced Uncoupling protein 1 levels in WAT under both basal and cold conditions. SPX also reduced cox8b and pgc1α mRNA levels and mitochondrial DNA, principally in IAT. SPX did not modulate the number of beige precursors. SPX decreased spx levels in IAT depots and galr2 in WAT depots. No differences were observed in the BAT depots. In conclusion, we showed, for the first time, that SPX treatment in vivo reduced the thermogenic process in subcutaneous and abdominal AT, being more evident under cold stimulation.

Echinacoside stimulates myogenesis and ATP-dependent thermogenesis in the skeletal muscle via the activation of D1-like dopaminergic receptors.

Recent studies have shown that some natural compounds from plants prevent obesity and related disorders, including the loss of skeletal muscle mass and strength. In this study, we investigated the effect of echinacoside (ECH), a caffeic acid glycoside from the phenylpropanoid class, on myogenesis and ATP-dependent thermogenesis in the skeletal muscle and its interaction with the dopaminergic receptors 1 and 5 (DRD1 and DRD5). We applied RT-PCR, immunoblot analysis, a staining method, and an assay kit to determine the effects of ECH on diverse target genes and proteins involved in skeletal muscle myogenesis and ATP-consuming futile processes. Our study demonstrated that ECH enhanced myogenic differentiation, glucose, and fatty acid uptake, as well as lipid catabolism, and induced ATP-dependent thermogenesis in vitro and in vivo. Moreover, ECH upregulated mitochondrial biogenesis proteins, mitochondrial oxidative phosphorylation (OXPHOS) complexes, and intracellular Ca2+ signaling as well as thermogenic proteins. These findings were further elucidated by mechanistic studies which showed that ECH mediates myogenesis via the DRD1/5 in C2C12 muscle cells. In addition, ECH stimulates α1-AR-mediated ATP-dependent thermogenesis via the DRD1/5/cAMP/SLN/SERCA1a pathway in C2C12 muscle cells. To the best of our knowledge, this is the first report that demonstrates the myogenic and thermogenic potential of ECH activity through the dopaminergic receptors. Understanding the novel functions of ECH in terms of its ability to prevent skeletal muscle loss and energy expenditure via ATP-consuming futile processes could help to develop potential alternative strategies to address muscle-related diseases, including combating obesity.

SCD1 sustains brown fat sympathetic innervation and thermogenesis during the long-term cold exposure.

Brown fat adipose tissue (BAT) is a therapeutic potential target to improve obesity, diabetes and cold acclimation in mammals. During the long-term cold exposure, the hyperplastic sympathetic network is crucial for BAT the maintain the highly thermogenic status. It has been proved that the sympathetic nervous drives the thermogenic activity of BAT via the release of norepinephrine. However, it is still unclear that how the thermogenic BAT affects the remodeling of the hyperplastic sympathetic network, especially during the long-term cold exposure. Here, we showed that following long-term cold exposure, SCD1-mediated monounsaturated fatty acid biosynthesis pathway was enriched, and the ratios of monounsaturated/saturated fatty acids were significantly up-regulated in BAT. And SCD1-deficiency in BAT decreased the capacity of cold acclimation, and suppressed long-term cold mediated BAT thermogenic activation. Furthermore, by using thermoneutral exposure and sympathetic nerve excision models, we disclosed that SCD1-deficiency in BAT affected the thermogenic activity, depended on sympathetic nerve. In mechanism, SCD1-deficiency resulted in the unbalanced ratio of palmitic acid (PA)/palmitoleic acid (PO), with obviously higher level of PA and lower level of PO. And PO supplement efficiently reversed the inhibitory role of SCD1-deficiency on BAT thermogenesis and the hyperplastic sympathetic network. Thus, our data provided insight into the role of SCD1-mediated monounsaturated fatty acids metabolism to the interaction between thermogenic activity BAT and hyperplastic sympathetic networks, and illustrated the critical role of monounsaturated fatty acids biosynthetic pathway in cold acclimation during the long-term cold exposure.

In vivo heat production dynamics during a contraction-relaxation cycle in rat single skeletal muscle fibers.

Skeletal muscle generates heat via contraction-dependent (shivering) and independent (nonshivering) mechanisms. While this thermogenic capacity of skeletal muscle undoubtedly contributes to the body temperature homeostasis of animals and impacts various cellular functions, the intracellular temperature and its dynamics in skeletal muscle in vivo remain elusive. We aimed to determine the intracellular temperature and its changes within skeletal muscle in vivo during contraction and following relaxation. In addition, we tested the hypothesis that sarcoplasmic reticulum Ca2+ ATPase (SERCA) generates heat and increases the myocyte temperature during a transitory Ca2+-induced contraction-relaxation cycle. The intact spinotrapezius muscle of anesthetized adult male Wistar rats (n = 18) was exteriorized and loaded with the fluorescent probe Cellular Thermoprobe for Fluorescence Ratio (49.3 µM) by microinjection over 1 s. The fluorescence ratio (i.e., 580 nm/515 nm) was measured in vivo during 1) temperature increases induced by means of an external heater, and 2) Ca2+ injection (3.9 nL, 2.0 mM). The fluorescence ratio increased as a linear function of muscle surface temperature from 25 °C to 40 °C (r2 = 0.97, P < 0.01). Ca2+ injection (3.9 nL, 2.0 mM) significantly increased myocyte intracellular temperature: An effect that was suppressed by SERCA inhibition with cyclopiazonic acid (CPA, Ca2+: 38.3 ± 1.4 °C vs Ca2++CPA: 28.3 ± 2.8 °C, P < 0.01 at 1 min following injection). While muscle shortening occurred immediately after the Ca2+ injection, the increased muscle temperature was maintained during the relaxation phase. In this investigation, we demonstrated a novel model for measuring the intracellular temperature of skeletal muscle in vivo and further that heat generation occurs concomitant principally with SERCA functioning and muscle relaxation.

A newly identified compound activating UCP1 inhibits obesity and its related metabolic disorders.

OBJECTIVE: Promoting thermogenesis in adipose tissue has been a promising strategy against obesity and related metabolic complications. We aimed to identify compounds that promote thermogenesis in adipocytes and to elucidate their functions and roles in metabolism. METHODS: To identify compounds that directly promote thermogenesis from a structurally diverse set of 4800 compounds, we utilized a cell-based platform for high-throughput screening that induces uncoupling protein 1 (Ucp1) expression in adipocytes. RESULTS: We identified one candidate compound that activates UCP1. Additional characterization of this compound revealed that it induced cellular thermogenesis in adipocytes with negligible cytotoxicity. In a subsequent diet-induced obesity model, mice treated with this compound exhibited a slower rate of weight gain, improved insulin sensitivity, and increased energy expenditure. Mechanistic studies have revealed that this compound increases mitochondrial biogenesis by elevating maximal respiration, which is partly mediated by the protein kinase A (PKA)-p38 mitogen-activated protein kinase (MAPK) signaling pathway. A further comprehensive genetic analysis of adipocytes treated with these compounds identified two novel UCP1-dependent thermogenic genes, potassium voltage-gated channel subfamily C member 2 (Kcnc2) and predicted gene 5627 (Gm5627). CONCLUSIONS: The identified compound can serve as a potential therapeutic drug for the treatment of obesity and its related metabolic disorders. Furthermore, our newly clarified thermogenic genes play an important role in UCP1-dependent thermogenesis in adipocytes.

Dose-dependent nonthermal modulation of whole body heat exchange during dynamic exercise in humans.

To maintain heat balance during exercise, humans rely on skin blood flow and sweating to facilitate whole body dry and evaporative heat exchange. These responses are modulated by the rise in body temperature (thermal factors), as well as several nonthermal factors implicated in the cardiovascular response to exercise (i.e., central command, mechanoreceptors, and metaboreceptors). However, the way these nonthermal factors interact with thermal factors to maintain heat balance remains poorly understood. We therefore used direct calorimetry to quantify the effects of dose-dependent increases in the activation of these nonthermal stimuli on whole body dry and evaporative heat exchange during dynamic exercise. In a randomized crossover design, eight participants performed 45-min cycling at a fixed metabolic heat production (200 W/m2) in warm, dry conditions (30°C, 20% relative humidity) on four separate occasions, differing only in the level of lower-limb compression applied via bilateral thigh cuffs pressurized to 0, 30, 60, or 90 mmHg. This model provoked increments in nonthermal activation while ensuring the heat loss required to balance heat production was matched across trials. At end-exercise, dry heat loss was 2 W/m2 [1, 3] lower per 30-mmHg pressure increment (P = 0.006), whereas evaporative heat loss was elevated 5 W/m2 [3, 7] with each pressure increment (P < 0.001). Body heat storage and esophageal temperature did not differ across conditions (both P ≥ 0.600). Our findings indicate that the nonthermal factors engaged during exercise exert dose-dependent, opposing effects on whole body dry and evaporative heat exchange, which do not significantly alter heat balance.NEW & NOTEWORTHY To maintain heat balance during exercise, humans rely on skin blood flow and sweating to facilitate dry and evaporative heat exchange. These responses are modulated by body temperatures (thermal factors) and several nonthermal factors (e.g., central command, metaboreceptors), although the way thermal and nonthermal factors interact to regulate body temperature is poorly understood. We demonstrate that nonthermal factors exert dose-dependent, opposing effects on dry and evaporative heat loss, without altering heat storage during dynamic exercise.

Adipose tissue browning and thermogenesis under physiologically energetic challenges: a remodelled thermogenic system.

Metabolic diseases such as obesity and diabetes are often thought to be caused by reduced energy expenditure, which poses a serious threat to human health. Cold exposure, exercise and caloric restriction have been shown to promote adipose tissue browning and thermogenesis. These physiological interventions increase energy expenditure and thus have emerged as promising strategies for mitigating metabolic disorders. However, that increased adipose tissue browning and thermogenesis elevate thermogenic consumption is not a reasonable explanation when humans and animals confront energetic challenges imposed by these interventions. In this review, we collected numerous results on adipose tissue browning and whitening and evaluated this bi-directional conversion of adipocytes from the perspective of energy homeostasis. Here, we propose a new interpretation of the role of adipose tissue browning under energetic challenges: increased adipose tissue browning and thermogenesis under energy challenge is not to enhance energy expenditure, but to reestablish a more economical thermogenic pattern to maintain the core body temperature. This can be achieved by enhancing the contribution of non-shivering thermogenesis (adipose tissue browning and thermogenesis) and lowering shivering thermogenesis and high intensity shivering. Consequently, the proportion of heat production in fat increases and that in skeletal muscle decreases, enabling skeletal muscle to devote more energy reserves to overcoming environmental stress.

Content of stress granules reveals a sex difference at the early phase of cold exposure in mice.

Adaptive thermogenesis is a vital physiological process for small endotherms. Female animals usually are more sensitive to cold temperature due to anatomical differences. Whether there is a sex difference at a molecular level is unclear. Stress granules (SGs) are dynamic organelles in which untranslated mRNAs reside during cellular stress. We hypothesize that the prompt response of SGs to cold stress can reveal the molecular difference between sexes. By analyzing the content in SGs of brown adipose tissue (BAT) at the early phase of cold stress for both sexes, we found more diverse mRNAs docked in the SGs in male mice and these mRNAs representing an extensive cellular reprogramming including apoptosis process and cold-induced thermogenesis. In female mice, the mRNAs in SGs dominantly were comprised of genes regulating ribonucleoprotein complex biogenesis. Conversely, the proteome in SGs was commonly characterized as structure molecules and RNA processing for both sexes. A spectrum of eukaryotic initiation factors (eIFs) was detected in the SGs of both female and male BAT, while those remained unchanged upon cold stress in male mice, various eIF3 and eIF4G isoforms were found reduced in female mice. Taken together, the unique features in SGs of male BAT reflected a prompt uncoupling protein-1 (UCP1) induction which was absent in female, and female, by contrast, were prepared for long-term transcriptional and translational adaptations.NEW & NOTEWORTHY The proteome analysis reveals that stress granules are the predominant form of cytosolic messenger ribonucleoproteins of brown adipose tissue (BAT) at the early phase of cold exposure in mice for both sexes. The transcriptome of stress granules of BAT unveils a sex difference of molecular response in early phase of cold exposure in mice, and such difference prepares for a prompt response to cold stress in male mice while for long-term adaptation in female mice.

Immunomodulatory leptin receptor+ sympathetic perineurial barrier cells protect against obesity by facilitating brown adipose tissue thermogenesis.

Adipose tissues (ATs) are innervated by sympathetic nerves, which drive reduction of fat mass via lipolysis and thermogenesis. Here, we report a population of immunomodulatory leptin receptor-positive (LepR+) sympathetic perineurial barrier cells (SPCs) present in mice and humans, which uniquely co-express Lepr and interleukin-33 (Il33) and ensheath AT sympathetic axon bundles. Brown ATs (BATs) of mice lacking IL-33 in SPCs (SPCΔIl33) had fewer regulatory T (Treg) cells and eosinophils, resulting in increased BAT inflammation. SPCΔIl33 mice were more susceptible to diet-induced obesity, independently of food intake. Furthermore, SPCΔIl33 mice had impaired adaptive thermogenesis and were unresponsive to leptin-induced rescue of metabolic adaptation. We therefore identify LepR+ SPCs as a source of IL-33, which orchestrate an anti-inflammatory BAT environment, preserving sympathetic-mediated thermogenesis and body weight homeostasis. LepR+IL-33+ SPCs provide a cellular link between leptin and immune regulation of body weight, unifying neuroendocrinology and immunometabolism as previously disconnected fields of obesity research.

Brown adipose tissue-derived metabolites and their role in regulating metabolism.

The discovery and rejuvenation of metabolically active brown adipose tissue (BAT) in adult humans have offered a new approach to treat obesity and metabolic diseases. Beyond its accomplished role in adaptive thermogenesis, BAT secretes signaling molecules known as "batokines", which are instrumental in regulating whole-body metabolism via autocrine, paracrine, and endocrine action. In addition to the intrinsic BAT metabolite-oxidizing activity, the endocrine functions of these molecules may help to explain the association between BAT activity and a healthy systemic metabolic profile. Herein, we review the evidence that underscores the significance of BAT-derived metabolites, especially highlighting their role in controlling physiological and metabolic processes involving thermogenesis, substrate metabolism, and other essential biological processes. The conversation extends to their capacity to enhance energy expenditure and mitigate features of obesity and its related metabolic complications. Thus, metabolites derived from BAT may provide new avenues for the discovery of metabolic health-promoting drugs with far-reaching impacts. This review aims to dissect the complexities of the secretory role of BAT in modulating local and systemic metabolism in metabolic health and disease.

The splicing factor SF3B1 is involved in brown adipocyte thermogenic activation.

The ability of alternative splicing mechanisms to control gene expression is increasingly being recognized as relevant for adipose tissue function. The expression of SF3B1, a key component of the SF3B complex directly involved in spliceosome formation, was previously reported to be significantly induced in brown adipose tissue under cold-induced thermogenic activation. Here, we identify that noradrenergic cAMP-mediated thermogenic stimulation increases SF3B1 expression in brown and beige adipocytes. We further show that pladienolide-B, a drug that binds SF3B1 to inhibit pre-mRNA splicing by targeting the SF3B complex, down-regulates key components of the thermogenic machinery (e.g., UCP1 gene expression), differentially alters the expression of alternative splicing-regulated transcripts encoding molecular actors involved in the oxidative metabolism of brown adipocytes (e.g., peroxisome proliferator-activated receptor-gamma co-activator-alpha [PGC-1α] and cytochrome oxidase subunit 7a genes), and impairs the respiratory activity of brown adipocytes. Similar alterations were found in brown adipocytes with siRNA-mediated knockdown of SF3B1 protein levels. Our findings collectively indicate that SF3B1 is a key factor in the appropriate thermogenic activation of differentiated brown adipocytes. This work exemplifies the importance of splicing processes in adaptive thermogenesis and suggests that pharmacological tools, such as pladienolide-B, may be used to modulate brown adipocyte thermogenic activity.

Thyroid Hormones Regulate the Thermoregulatory Mechanisms of the Body: Review.

Thyroid hormones (TH) play a critical role in metabolism, energy balance and thermogenesis. The mechanisms whereby thyroid hormone increases heat production have been analyzed with emphasis in more recent developments. Thyroid hormone increases obligatory thermogenesis as a result of the stimulation of numerous metabolic pathways involved in the development, remodeling and delivery of energy to the tissues. In this section, alterations in primary hyperthyroidism and hypothyroidism will be contrasted with the physiological characteristics of TH-dependent regulation in response to fasting and exposure to cold. The current review will discuss the situation with regard to regional thyroid hormones in the Central Nervous System (CNS) and more specifically, in peripheral cells. When caused by exposure to cold or fasting, local anomalies in the CNS are distinct from peripheral compartments, in contrast to hyperthyroidism and hypothyroidism, which differ when similar changes are observed. Lower hypothalamic TH concentrations are associated with cold exposure, although higher peripheral TH levels. The TH tendency is reversed by fasting. Primary hypothyroidism and hyperthyroidism impair them. The current study aims to trace the various mechanisms used by the thyroid gland to regulate the body's energy production process.

The Enhancement of Acylcarnitine Metabolism by 5-Heptadecylresorcinol in Brown Adipose Tissue Contributes to Improving Glucose and Lipid Levels in Aging Male Mice.

5-Heptadecylresorcinol (AR-C17), a primary biomarker of whole grain (WG) consumption, has been demonstrated to improve the thermogenic activity of aging mice. However, the intricate regulatory mechanism is not fully understood. This study conducted metabolomics analysis on young and aging mice with or without AR-C17 administration after cold exposure. The results showed that the aging mice displayed lower levels of acylcarnitine (ACar) in their plasma compared with the young mice during cold exposure, and 150 mg/kg/day of AR-C17 administration for 8 weeks could increase the plasma ACar levels of aging mice. ACar has been reported to be an essential metabolic fuel for the thermogenesis of brown adipose tissue (BAT). AR-C17 had similar effects on the ACar levels in the BAT as on the plasma of the aging mice during cold exposure. Furthermore, the aging mice had reduced ACar metabolism in the BAT, and AR-C17 could improve the ACar metabolism in the BAT of aging mice, thereby promoting the metabolic utilization of ACar by BAT. Moreover, the glucose and lipid levels of aging mice could be improved by AR-C17. This study revealed a deeper metabolic mechanism involved in the AR-C17-mediated thermogenic regulation of BAT, providing a new theoretical basis for the nutrition and health benefits of WG.

The secreted peptide BATSP1 promotes thermogenesis in adipocytes.

Although brown adipose tissue (BAT) has historically been viewed as a major site for energy dissipation through thermogenesis, its endocrine function has been increasingly recognized. However, the circulating factors in BAT that play a key role in controlling systemic energy homeostasis remain largely unexplored. Here, we performed a peptidomic analysis to profile the extracellular peptides released from human brown adipocytes upon exposure to thermogenic stimuli. Specifically, we identified a secreted peptide that modulates adipocyte thermogenesis in a cell-autonomous manner, and we named it BATSP1. BATSP1 promoted BAT thermogenesis and induced browning of white adipose tissue in vivo, leading to increased energy expenditure under cold stress. BATSP1 treatment in mice prevented high-fat diet-induced obesity and improved glucose tolerance and insulin resistance. Mechanistically, BATSP1 facilitated the nucleocytoplasmic shuttling of forkhead transcription factor 1 (FOXO1) and released its transcriptional inhibition of uncoupling protein 1 (UCP1). Overall, we provide a comprehensive analysis of the human brown adipocyte extracellular peptidome following acute forskolin (FSK) stimulation and identify BATSP1 as a novel regulator of thermogenesis that may offer a potential approach for obesity treatment.