Browning of adipose tissue and increased thermogenesis induced by Methotrexate
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ABSTRACT:
SUBMITTER: Verma N
PROVIDER: S-EPMC8565234 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Accumulating evidence from both animal and human studies suggests that activation of beige fat increases cellular energy expenditure, ultimately reducing adiposity. Here, we report the central role of adipocyte-derived lysyl oxidase (Lox) in the formation of thermogenic beige fat. Mice exposed to cold or a β3 agonist showed drastically lower Lox expression in thermogenically activated beige fat. Importantly, inhibition of Lox activity with BAPN stimulated biogenesis of beige fat in inguinal white adipose tissue (iWAT) under housing conditions and potentiated cold-induced adaptive thermogenesis and beiging in both iWAT and epididymal white adipose tissue (eWAT). Notably, white adipocytes with Lox repression undergo transdifferentiation into beige adipocytes which can be suppressed by tumor necrosis factor-α (TNFα) via ERK activation. This work provides new insight into the molecular control to expand beige fat by Lox inhibition and suggest the potential for utilizing inhibitor of Lox to treat the emerging epidemics of obesity and diabetes.
| S-EPMC8720662 | biostudies-literature
Project description:Exercise training results in beneficial adaptations to numerous tissues and offers protection against metabolic disorders including obesity and type 2 diabetes. Multiple studies have indicated that both white (WAT) and brown (BAT) adipose tissue may play an important role to mediate the beneficial effects of exercise. Studies from both rodents and humans have identified exercise-induced changes in WAT including increased mitochondrial activity and glucose uptake, an altered endocrine profile, and in rodents, a beiging of the WAT. Studies investigating the effects of exercise on BAT have resulted in conflicting data in terms of mitochondrial activity, glucose uptake, and thermogenic activity in rodents and humans, and remain an important area of investigation. This review discusses the exercise-induced adaptations to white and brown adipose tissue, distinguishing important differences between rodents and humans and highlighting the latest studies in the field and their implications.
| S-EPMC7201000 | biostudies-literature
Project description:ObjectiveTransformation of white into brown fat ("browning") reduces obesity in many preclinical models and holds great promise as a therapeutic concept in metabolic disease. Vitamin A metabolites (retinoids) have been linked to thermogenic programming of adipose tissue; however, the physiologic importance of systemic retinoid transport for adipose tissue browning and adaptive thermogenesis is unknown.MethodsWe performed cold exposure studies in mice and humans and used a genetic model of defective vitamin A transport, the retinol binding protein deficient (Rbp-/-) mouse, to study the effects of cooling on systemic vitamin A and the relevance of intact retinoid transport on cold-induced adipose tissue browning.ResultsWe show that cold stimulation in mice and humans leads to an increase in circulating retinol and its plasma transporter, Rbp. In Rbp-/- mice, thermogenic programming of adipocytes and oxidative mitochondrial function are dramatically impaired in subcutaneous white fat, which renders Rbp-/- mice more cold-sensitive. In contrast, retinol stimulation in primary human adipocytes promotes thermogenic gene expression and mitochondrial respiration. In humans, cold-mediated retinol increase is associated with a shift in oxidative substrate metabolism suggestive of higher lipid utilisation.ConclusionsSystemic vitamin A levels are regulated by cold exposure in mice and humans, and intact retinoid transport is essential for cold-induced adipose tissue browning and adaptive thermogenesis.
| S-EPMC7585949 | biostudies-literature
Project description:Obesity results from increased energy intake or defects in energy expenditure. Brown adipose tissue (BAT) is specialized for energy expenditure, a process called adaptive thermogenesis. Peroxisome proliferator-activated receptor ? coactivator 1? (PGC1?) controls BAT-mediated thermogenesis by regulating the expression of Ucp1 Inhibitor of differentiation 1 (Id1) is a helix-loop-helix transcription factor that plays an important role in cell proliferation and differentiation. We demonstrate a novel function of Id1 in BAT thermogenesis and programming of beige adipocytes in white adipose tissue (WAT). We found that adipose tissue-specific overexpression of Id1 causes age-associated and high-fat diet-induced obesity in mice. Id1 suppresses BAT thermogenesis by binding to and suppressing PGC1? transcriptional activity. In WAT, Id1 is mainly localized in the stromal vascular fraction, where the adipose progenitor/precursors reside. Lack of Id1 increases beige gene and Ucp1 expression in the WAT in response to cold exposure. Furthermore, brown-like differentiation is increased in Id1-deficient mouse embryonic fibroblasts. At the molecular level, Id1 directly interacts with and suppresses Ebf2 transcriptional activity, leading to reduced expression of Prdm16, which determines beige/brown adipocyte cell fate. Overall, the study highlights the existence of novel regulatory mechanisms between Id1/PGC1? and Id1/Ebf2 in controlling brown fat metabolism, which has significant implications in the treatment of obesity and its associated diseases, such as diabetes.
| S-EPMC5440025 | biostudies-literature
Project description:The brown adipose tissue (BAT) is a thermogenic organ that plays a major role in energy balance, obesity, and diabetes due to the potent glucose and lipid clearance that fuels its thermogenesis, which is largely mediated via sympathetic nervous system activation. However, thus far there has been little experimental validation of the hypothesis that selective neuromodulation of the sympathetic nerves innervating the BAT is sufficient to elicit thermogenesis in mice. We generated mice expressing blue light-activated channelrhodopsin-2 (ChR2) in the sympathetic nerves innervating the BAT using two different strategies: injecting the BAT of C57Bl/6J mice with AAV6-hSyn-ChR2 (H134R)-EYFP; crossbreeding tyrosine hydroxylase-Cre mice with floxed-stop ChR2-EYFP mice. The nerves in the BAT expressing ChR2 were selectively stimulated with a blue LED light positioned underneath the fat pad of anesthetized mice, while the BAT and core temperatures were simultaneously recorded. Using immunohistochemistry we confirmed the selective expression of EYFP in TH positive nerves fibers. In addition, local optogenetic stimulation of the sympathetic nerves induced significant increase in the BAT temperature followed by an increase in core temperature in mice expressing ChR2, but not in the respective controls. The BAT activation was also paralleled by increased levels of pre-UCP1 transcript. Our results demonstrate that local optogenetic stimulation of the sympathetic nerves is sufficient to elicit BAT and core thermogenesis, thus suggesting that peripheral neuromodulation has the potential to be exploited as an alternative to pharmacotherapies to elicit organ activation and thus ameliorate type 2 diabetes and/or obesity.
| S-EPMC7306786 | biostudies-literature
Project description:Previous studies using genetic mouse models have implicated COX-2 in the browning of white adipose tissues (WATs) in mice during cold exposure. However, COX-2 is important during development, and conventional knockouts (KOs) exhibit many defects, conditioned by genetic background. Similarly, the physiological relevance of transgenic overexpression of COX-2 is questionable. In the present study, we utilized mice in which COX-2 was deleted postnatally, bypassing the consequences of enzyme deficiency during development. Despite activation of thermogenesis and browning of inguinal WAT, cold exposure failed to increase COX-2 expression in the adipose tissues of mice with different genetic backgrounds, and the body temperature response to cold was unaltered in postnatal global COX-2 KOs. Selective disruption of COX-2 in adipose tissues also failed detectably to impact systemic prostaglandin biosynthesis. Browning of inguinal WATs induced by exposure to cold is independent of adipose tissue COX-2.
| S-EPMC6118132 | biostudies-literature
Project description:Brown adipose tissue is responsible for facultative thermogenesis to produce heat and increase energy expenditure in response to proper stimuli, e.g., cold. Acquisition of brown-like features (browning) in perivascular white adipose tissue (PVAT) may protect against obesity/cardiovascular disease. Most browning studies are performed in rodents, but translation to humans would benefit from a closer animal model. Therefore, we studied the browning response of ferret thoracic aortic PVAT (tPVAT) to cold. We performed global transcriptome analysis of tPVAT of 3-month-old ferrets acclimatized 1 week to 22 or 4°C, and compared the results with those of inguinal subcutaneous adipose tissue. Immunohistochemistry was used to visualize browning. Transcriptome data revealed a stronger cold exposure response of tPVAT, including increased expression of key brown/brite markers, compared to subcutaneous fat. This translated into a clear white-to-brown remodeling of tPVAT, with the appearance of multilocular highly UCP1-stained adipocytes. The pathway most affected by cold exposure in tPVAT was immune response, characterized by down-regulation of immune-related genes, with cardio protective implications. On the other hand, subcutaneous fat responded to cold by increasing energy metabolism based on increased expression of fatty acid oxidation and tricarboxylic acid cycle genes, concordant with lower inguinal adipose tissue weight in cold-exposed animals. Thus, ferret tPVAT responds to cold acclimation with a strong induction of browning and immunosuppression compared to subcutaneous fat. Our results present ferrets as an accessible translational animal model displaying functional responses relevant for obesity and cardiovascular disease prevention.
| S-EPMC6759601 | biostudies-literature
Project description:Obesity is one of the most serious public health problems in the 21st century that may lead to many comorbidities such as type-2 diabetes, cardiovascular diseases, and cancer. Current treatments toward obesity including diet, physical exercise, pharmacological therapy, as well as surgeries are always associated with low effectiveness or undesired systematical side effects. In order to enhance treatment efficiency with minimized side effects, we developed a transcutaneous browning agent patch to locally induce adipose tissue transformation. This microneedle-based patch can effectively deliver browning agents to the subcutaneous adipocytes in a sustained manner and switch on the "browning" at the targeted region. It is demonstrated that this patch reduces treated fat pad size, increases whole body energy expenditure, and improves type-2 diabetes in vivo in a diet-induced obesity mouse model.
| S-EPMC6812556 | biostudies-literature
Project description:OBJECTIVES:Genome-wide association studies have reported that DNA polymorphisms at the CDKN2A locus modulate fasting glucose in human and contribute to type 2 diabetes (T2D) risk. Yet the causal relationship between this gene and defective energy homeostasis remains elusive. Here we sought to understand the contribution of Cdkn2a to metabolic homeostasis. METHODS:We first analyzed glucose and energy homeostasis from Cdkn2a-deficient mice subjected to normal or high fat diets. Subsequently Cdkn2a-deficient primary adipose cells and human-induced pluripotent stem differentiated into adipocytes were further characterized for their capacity to promote browning of adipose tissue. Finally CDKN2A levels were studied in adipocytes from lean and obese patients. RESULTS:We report that Cdkn2a deficiency protects mice against high fat diet-induced obesity, increases energy expenditure and modulates adaptive thermogenesis, in addition to improving insulin sensitivity. Disruption of Cdkn2a associates with increased expression of brown-like/beige fat markers in inguinal adipose tissue and enhances respiration in primary adipose cells. Kinase activity profiling and RNA-sequencing analysis of primary adipose cells further demonstrate that Cdkn2a modulates gene networks involved in energy production and lipid metabolism, through the activation of the Protein Kinase A (PKA), PKG, PPARGC1A and PRDM16 signaling pathways, key regulators of adipocyte beiging. Importantly, CDKN2A expression is increased in adipocytes from obese compared to lean subjects. Moreover silencing CDKN2A expression during human-induced pluripotent stem cells adipogenic differentiation promoted UCP1 expression. CONCLUSION:Our results offer novel insight into brown/beige adipocyte functions, which has recently emerged as an attractive therapeutic strategy for obesity and T2D. Modulating Cdkn2a-regulated signaling cascades may be of interest for the treatment of metabolic disorders.
| S-EPMC5985036 | biostudies-literature
Project description:Skeletal muscle has been suggested as a site of nonshivering thermogenesis (NST) besides brown adipose tissue (BAT). Studies in birds, which do not contain BAT, have demonstrated the importance of skeletal muscle-based NST. However, muscle-based NST in mammals remains poorly characterized. We recently reported that sarco/endoplasmic reticulum Ca(2+) cycling and that its regulation by SLN can be the basis for muscle NST. Because of the dominant role of BAT-mediated thermogenesis in rodents, the role of muscle-based NST is less obvious. In this study, we investigated whether muscle will become an important site of NST when BAT function is conditionally minimized in mice. We surgically removed interscapular BAT (iBAT, which constitutes ?70% of total BAT) and exposed the mice to prolonged cold (4 °C) for 9 days. The iBAT-ablated mice were able to maintain optimal body temperature (?35-37 °C) during the entire period of cold exposure. After 4 days in the cold, both sham controls and iBAT-ablated mice stopped shivering and resumed routine physical activity, indicating that they are cold-adapted. The iBAT-ablated mice showed higher oxygen consumption and decreased body weight and fat mass, suggesting an increased energy cost of cold adaptation. The skeletal muscles in these mice underwent extensive remodeling of both the sarcoplasmic reticulum and mitochondria, including alteration in the expression of key components of Ca(2+) handling and mitochondrial metabolism. These changes, along with increased sarcolipin expression, provide evidence for the recruitment of NST in skeletal muscle. These studies collectively suggest that skeletal muscle becomes the major site of NST when BAT activity is minimized.
| S-EPMC5016124 | biostudies-literature