Inguinal White Adipose Tissue Research Articles

Uncoupling protein 1-driven Cre (Ucp1-Cre) is expressed in the epithelial cells of mammary glands and various non-adipose tissues

ObjectiveUncoupling protein 1 (UCP1), a mitochondrial protein responsible for nonshivering thermogenesis in adipose tissue, serves as a distinct marker for thermogenic brown and beige adipocytes. Ucp1-Cre mice are thus widely used to genetically manipulate these thermogenic adipocytes. However, evidence suggests that UCP1 may also be expressed in non-adipocyte cell types. In this study, we investigated the presence of UCP1 expression in different mouse tissues that have not been previously reported. MethodsWe employed Ucp1-Cre mice crossed with Cre-inducible transgenic reporter Nuclear tagging and Translating Ribosome Affinity Purification (NuTRAP) mice to investigate Ucp1-Cre expression in various tissues of adult female mice and developing embryos. Tamoxifen-inducible Ucp1-CreERT2 mice crossed with NuTRAP mice were used to assess active Ucp1 expression in adult mice. Immunostaining, RNA analysis, and single-cell/nucleus RNA-seq (sc/snRNA-seq) data analysis were performed to determine the expression of endogenous UCP1 and Ucp1-Cre-driven reporter expression. We also investigated the impact of UCP1 deficiency on mammary gland development and function using Ucp1-knockout (KO) mice. ResultsUcp1-Cre expression was observed in the mammary glands within the inguinal white adipose tissue of female Ucp1-Cre; NuTRAP mice. Ucp1-Cre was activated during embryonic development in various tissues, including mammary glands, as well as in the brain, kidneys, eyes, and ears, specifically in epithelial cells in these organs. However, Ucp1-CreERT2 showed no or only partial activation in these tissues of adult mice, indicating the potential for low or transient expression of endogenous Ucp1. While sc/snRNA-seq data suggest potential expression of UCP1 in mammary epithelial cells in adult mice and humans, Ucp1-KO female mice displayed normal mammary gland development and function. ConclusionsOur findings reveal widespread Ucp1-Cre expression in various non-adipose tissue types, starting during early development. These results highlight the importance of exercising caution when interpreting data and devising experiments involving Ucp1-Cre mice.

Development of Recombinant High-Density Lipoprotein Platform with Innate Adipose Tissue-Targeting Abilities for Regional Fat Reduction.

As an escalating public health issue, obesity and overweight conditions are predispositions to various diseases and are exacerbated by concurrent chronic inflammation. Nonetheless, extant antiobesity pharmaceuticals (quercetin, capsaicin, catecholamine, etc.) manifest constrained efficacy alongside systemic toxic effects. Effective therapeutic approaches that selectively target adipose tissue, thereby enhancing local energy expenditure, surmounting the limitations of prevailing antiobesity modalities are highly expected. In this context, we developed a temperature-sensitive hydrogel loaded with recombinant high-density lipoprotein (rHDL) to achieve targeted delivery of resveratrol, an adipose browning activator, to adipose tissue. rHDL exhibits self-regulation on fat cell metabolism and demonstrates natural targeting toward scavenger receptor class B type I (SR-BI), which is highly expressed by fat cells, thereby achieving a synergistic effect for the treatment of obesity. Additionally, the dispersion of rHDL@Res in temperature-sensitive hydrogels, coupled with the regulation of their degradation and drug release rate, facilitated sustainable drug release at local adipose tissues over an extended period. Following 24 days' treatment regimen, obese mice exhibited improved metabolic status, resulting in a reduction of 68.2% of their inguinal white adipose tissue (ingWAT). Specifically, rHDL@Res/gel facilitated the conversion of fatty acids to phospholipids (PA, PC), expediting fat mobilization, mitigating triglyceride accumulation, and therefore facilitating adipose tissue reduction. Furthermore, rHDL@Res/gel demonstrated efficacy in attenuating obesity-induced inflammation and fostering angiogenesis in ingWAT. Collectively, this engineered local fat reduction platform demonstrated heightened effectiveness and safety through simultaneously targeting adipocytes, promoting WAT browning, regulating lipid metabolism, and controlling inflammation, showing promise for adipose-targeted therapy.

SLC25A28 Overexpression Promotes Adipogenesis by Reducing ATGL.

Adipose tissue dysfunction is seen among obese and type 2 diabetic individuals. Adipocyte proliferation and hypertrophy are the root causes of adipose tissue expansion. Solute carrier family 25 member 28 (SLC25A28) is an iron transporter in the inner mitochondrial membrane. This study is aimed at validating the involvement of SLC25A28 in adipose accumulation by tail vein injection of adenovirus (Ad)-SLC25A28 and Ad-green fluorescent protein viral particles into C57BL/6J mice. After 16 weeks, the body weight of the mice was measured. Subsequently, morphological analysis was performed to establish a high-fat diet (HFD)-induced model. SLC25A28 overexpression accelerated lipid accumulation in white and brown adipose tissue (BAT), enhanced body weight, reduced serum triglyceride (TG), and impaired serum glucose tolerance. The protein expression level of lipogenesis, lipolysis, and serum adipose secretion hormone was evaluated by western blotting. The results showed that adipose TG lipase (ATGL) protein expression was reduced significantly in white and BAT after overexpression SLC25A28 compared to the control group. Moreover, SLC25A28 overexpression inhibited the BAT formation by downregulating UCP-1 and the mitochondrial biosynthesis marker PGC-1α. Serum adiponectin protein expression was unregulated, which was consistent with the expression in inguinal white adipose tissue (iWAT). Remarkably, serum fibroblast growth factor (FGF21) protein expression was negatively related to the expansion of adipose tissue after administrated by Ad-SLC25A28. Data from the current study indicate that SLC25A28 overexpression promotes diet-induced obesity and accelerates lipid accumulation by regulating hormone secretion and inhibiting lipolysis in adipose tissue.

Epigenetically active chromatin in neonatal iWAT reveals GABPα as a potential regulator of beige adipogenesis.

Thermogenic beige adipocytes, which dissipate energy as heat, are found in neonates and adults. Recent studies show that neonatal beige adipocytes are highly plastic and contribute to >50% of beige adipocytes in adults. Neonatal beige adipocytes are distinct from recruited beige adipocytes in that they develop independently of temperature and sympathetic innervation through poorly defined mechanisms. We characterized the neonatal beige adipocytes in the inguinal white adipose tissue (iWAT) of C57BL6 postnatal day 3 and 20 mice (P3 and P20) by imaging, genome-wide RNA-seq analysis, ChIP-seq analysis, qRT-PCR validation, and biochemical assays. We found an increase in acetylated histone 3 lysine 27 (H3K27ac) on the promoter and enhancer regions of beige-specific gene UCP1 in iWAT of P20 mice. Furthermore, H3K27ac ChIP-seq analysis in the iWAT of P3 and P20 mice revealed strong H3K27ac signals at beige adipocyte-associated genes in the iWAT of P20 mice. The integration of H3K27ac ChIP-seq and RNA-seq analysis in the iWAT of P20 mice reveal epigenetically active signatures of beige adipocytes, including oxidative phosphorylation and mitochondrial metabolism. We identify the enrichment of GA-binding protein alpha (GABPα) binding regions in the epigenetically active chromatin regions of the P20 iWAT, particularly on beige genes, and demonstrate that GABPα is required for beige adipocyte differentiation. Moreover, transcriptomic analysis and glucose oxidation assays revealed increased glycolytic activity in the neonatal iWAT from P20. Our findings demonstrate that epigenetic mechanisms regulate the development of peri-weaning beige adipocytes via GABPα. Further studies to better understand the upstream mechanisms that regulate epigenetic activation of GABPα and characterization of the metabolic identity of neonatal beige adipocytes will help us harness their therapeutic potential in metabolic diseases.

Alpha-Lipoic Acid Induces Adipose Tissue Browning through AMP-Activated Protein Kinase Signaling in Vivo and in Vitro.

AMP-activated protein kinase (AMPK) is a key enzyme for cellular energy homeostasis and improves metabolic disorders. Brown and beige adipose tissues exert thermogenesis capacities to dissipate energy in the form of heat. Here, we investigated the beneficial effects of the antioxidant alpha-lipoic acid (ALA) in menopausal obesity and the underlying mechanisms. Female Wistar rats (8 weeks old) were subjected to bilateral ovariectomy (Ovx) and divided into four groups: Sham (n=8), Ovx (n=11), Ovx+ALA2 (n=10), and Ovx+ALA3 (n=6) (ALA 200 and 300 mg/kg/day, respectively; gavage) for 8 weeks. 3T3-L1 cells were used for in vitro study. Rats receiving ALA2 and ALA3 treatment showed significantly lower levels of body weight and white adipose tissue (WAT) mass than those of the Ovx group. ALA improved plasma lipid profiles including triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Hematoxylin & eosin staining of inguinal WAT showed that ALA treatment reduced Ovx-induced adipocyte size and enhanced uncoupling protein 1 (UCP1) expression. Moreover, plasma levels of irisin were markedly increased in ALA-treated Ovx rats. Protein expression of brown fat-specific markers including UCP1, PRDM16, and CIDEA was downregulated by Ovx but markedly increased by ALA. Phosphorylation of AMPK, its downstream acetyl-CoA carboxylase, and its upstream LKB1 were all significantly increased by ALA treatment. In 3T3-L1 cells, administration of ALA (100 and 250 μM) reduced lipid accumulation and enhanced oxygen consumption and UCP1 protein expression, while inhibition of AMPK by dorsomorphin (5 μM) significantly reversed these effects. ALA improves estrogen deficiency-induced obesity via browning of WAT through AMPK signaling.

Epigallocatechin gallate protects against fat and muscle atrophy in B16BL6 melanoma-bearing mice on a high-fat diet

AimsEpidemiological evidence indicates that there is a substantial association between body mass index (BMI) and at least ten forms of cancer, including melanoma, and BMI imbalance contributes to the poor survival rate of cancer patients before and after therapy. Nevertheless, few pharmacological studies on models of obesity and cancer have been reported. In this study, we administered epigallocatechin gallate (EGCG) to B16BL6 tumor-bearing mice that received a high-fat diet (HFD) to examine its impact. MethodsB16BL6 tumor-bearing mice were fed a HFD. Body weight and food intake were documented every week. We conducted a Western blot analysis to examine the protein levels in the tumor, gastrocnemius (GAS), and tibialis anterior (TA) muscles, as well as the inguinal and epididymal white adipose tissues (iWAT and eWAT). Key findingsEGCG has been shown to have anti-cancer effects equivalent to those of cisplatin, a chemotherapy drug. Furthermore, EGCG protected against the loss of epidydimal white adipose tissue by regulating protein levels of lipolysis factors of adipose triglyceride lipase and hormone-sensitive lipase as well as WAT browning factors of uncoupling protein 1, as opposed to cisplatin. EGCG was shown to reduce the protein levels of muscular atrophy factors of muscle RING-finger protein-1, whereas cisplatin did not contribute to rescuing the atrophy of TA and GAS muscles. ConclusionTaken together, our findings indicate that EGCG has a preventive effect against cachexia symptoms and has anti-cancer effects similar to those of cisplatin in tumor-bearing mice fed a high-fat diet.

Glucose regulation of adipose tissue browning by CBP/p300- and HDAC3-mediated reversible acetylation of CREBZF

Glucose is required for generating heat during cold-induced nonshivering thermogenesis in adipose tissue, but the regulatory mechanism is largely unknown. CREBZF has emerged as a critical mechanism for metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD). We investigated the roles of CREBZF in the control of thermogenesis and energy metabolism. Glucose induces CREBZF in human white adipose tissue (WAT) and inguinal WAT (iWAT) in mice. Lys208 acetylation modulated by transacetylase CREB-binding protein/p300 and deacetylase HDAC3 is required for glucose-induced reduction of proteasomal degradation and augmentation of protein stability of CREBZF. Glucose induces rectal temperature and thermogenesis in white adipose of control mice, which is further potentiated in adipose-specific CREBZF knockout (CREBZF FKO) mice. During cold exposure, CREBZF FKO mice display enhanced thermogenic gene expression, browning of iWAT, and adaptive thermogenesis. CREBZF associates with PGC-1α to repress thermogenic gene expression. Expression levels of CREBZF are negatively correlated with UCP1 in human adipose tissues and increased in WAT of obese ob/ob mice, which may underscore the potential role of CREBZF in the development of compromised thermogenic capability under hyperglycemic conditions. Our results reveal an important mechanism of glucose sensing and thermogenic inactivation through reversible acetylation.

Glycogen synthesis is required for adaptive thermogenesis in beige adipose tissue and affects diet-induced obesity.

Glycogen is a form of energy storage for glucose in different tissues such as liver and skeletal muscle. It remains incompletely understood how glycogen impacts on adipose tissue functionality. Cold exposure elevated the expression of Gys1 that encodes glycogen synthase 1 in brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT). The in vivo function of Gys1 was analyzed using a mouse model in which Gys1 was deleted specifically in adipose tissues. Under normal chow conditions, Gys1 deletion caused little changes to body weight and glucose metabolism. Deletion of Gys1 abrogated upregulation of UCP1 and other thermogenesis-related genes in iWAT upon prolonged cold exposure or treatment with β3-adrenergic receptor agonist CL-316,243. Stimulation of UCP1 by CL-316,243 in adipose-derived stromal cells (stromal vascular fractions, SVFs) was also reduced by Gys1 deletion. Both the basal glycogen content and CL-316,243-stimulated glycogen accumulation in adipose tissues were reduced by Gys1 deletion. High-fat diet-induced obesity and insulin resistance were aggravated in Gys1-deleted mice. The loss of body weight upon CL-316,243 treatment was also abrogated by the loss of Gys1. In conclusion, our results underscore the pivotal role of glycogen synthesis in adaptive thermogenesis in beige adipose tissue and its impact on diet-induced obesity in mice.NEW & NOTEWORTHY Glycogen is one of major types of fuel reserve in the body and its classical function is to maintain blood glucose level. This study uncovers that glycogen synthesis is required for beige fat tissue to generate heat upon cold exposure. Such a function of glycogen is linked to development of high-fat diet-induced obesity, thus extending our understanding about the physiological functions of glycogen.

Transplantation of Cold-Stimulated Subcutaneous Adipose Tissue Improves Fat Retention and Recipient Metabolism.

Induction of beige fat for grafting is an emerging transplantation strategy. However, safety concerns associated with pharmaceutical interventions limits its wider application. Moreover, as a special type of fat with strong metabolic functions, the effect of metabolism of recipients after beige fat grafting has not been explored in plastic surgery domain. To explore whether cold-induced inguinal white adipose tissue(iWAT) transplantation has a higher retention rate and beneficial effects on recipient metabolism. The mice were subjected to cold stimulation for 48 hours to induce the browning of iWAT and harvested immediately. Subsequently, each C57/BL6 mouse received 0.2 ml cold-induced iWAT or normal iWAT transplantation. Fat grafts and recipients' iWAT, epididymal adipose tissue (epiWAT) and brown adipose tissue (BAT) were harvested at 8 weeks after operation. Immunofluorescence staining, real-time PCR and western blot were used for histological and molecular analysis. Cold-induced iWAT grafting has a higher retention rate (67.33%±1.74% vs. 55.83% ± 2.94%, P < 0.01) and more satisfactory structural integrity. Histological changes identified the better adipose tissue homeostasis after cold challenge, including abundant smaller adipocytes, higher levels of adipogenesis, angiogenesis, and proliferation, but lower levels of fibrosis. More importantly, cold-induced iWAT grafting suppressed the inflammation of epiWAT caused by conventional fat grafting, and activated the glucose metabolism and thermogenic activity of recipients' adipose tissues. Cold-induced iWAT grafting was an effective non-pharmacological intervention strategy to improve the retention rate and grafts' homeostasis. Furthermore, it improved the adverse effects caused by traditional fat grafting, but bring metabolic benefits.

Dexamethasone Inhibits White Adipose Tissue Browning.

White adipose tissue (WAT) regulates energy balance through energy storage, adipokines secretion and the thermogenesis process. Beige adipocytes are responsible for WAT thermogenesis. They are generated by adipogenesis or transdifferentiation during cold or β3-adrenergic agonist stimulus through a process called browning. Browning has gained significant interest for to its preventive effect on obesity. Glucocorticoids (GCs) have several functions in WAT biology; however, their role in beige adipocyte generation and WAT browning is not fully understood. The aim of our study was to determine the effect of dexamethasone (DXM) on WAT thermogenesis. For this purpose, rats were treated with DXM at room temperature (RT) or cold conditions to determine different thermogenic markers. Furthermore, the effects of DXM on the adipogenic potential of beige precursors and on mature beige adipocytes were evaluated in vitro. Our results showed that DXM decreased UCP-1 mRNA and protein levels, mainly after cold exposure. In vitro studies showed that DXM decreased the expression of a beige precursor marker (Ebf2), affecting their ability to differentiate into beige adipocytes, and inhibited the thermogenic response of mature beige adipocytes (Ucp-1, Dio2 and Pgc1α gene expressions and mitochondrial respiration). Overall, our data strongly suggest that DXM can inhibit the thermogenic program of both retroperitoneal and inguinal WAT depots, an effect that could be exerted, at least partially, by inhibiting de novo cell generation and the thermogenic response in beige adipocytes.

Cadmium exposure causes transcriptomic dysregulation in adipose tissue and associated shifts in serum metabolites

Cadmium (Cd) is a toxic heavy metal found in natural and industrial environments. Exposure to Cd can lead to various metabolic disturbances, notably disrupting glucose and lipid homeostasis. Despite this recognition, the direct impact of Cd exposure on lipid metabolism within adipose tissue, and the mechanisms underlying these effects, have not been fully elucidated. In this study, we found that Cd accumulates in adipose tissues of mice subjected to Cd exposure. Intriguingly, Cd exposure in itself did not induce significant alterations in the adipose tissue under normal conditions. However, when subjected to cold stimulation, several notable changes were observed in the mice exposed to Cd, including a reduction in the drop of body temperature, a decrease in the size of inguinal white adipose tissue (WAT), and an increase in the expression of thermogenic genes UCP1 and PRDM16. These results indicate that Cd exposure might enhance the responsiveness of adipose tissue to external stimuli and increase the energy expenditure of the tissue. RNA-seq analysis further revealed that Cd exposure altered gene expression profiles, particularly affecting peroxisome proliferator-activated receptor (PPAR)-mediated metabolic pathways, promoting metabolic remodeling in adipose tissue and resulting in the depletion of lipids stored in adipose tissue for energy. Non-targeted metabolomic analysis of mouse serum showed that Cd exposure significantly disrupted metabolites and significantly increased serum fatty acid and triglyceride levels. Correspondingly, population-level data confirmed an association between Cd exposure and elevated levels of serum total cholesterol, total triglycerides, and low-density lipoprotein cholesterol. In summary, we provide substantial evidence of the molecular events induced by Cd that are relevant to the regulation of lipid metabolism in adipose tissue. Our findings suggest that the toxic effects of Cd can impact adipocyte functionality, positioning adipose tissue as a critical target for metabolic diseases resulting from Cd exposure.

Conjugated linoleic acid (CLA) reduces HFD-induced obesity by enhancing BAT thermogenesis and iWAT browning via the CD36-AMPK pathway.

The antiobesity effect of conjugated linoleic acid (CLA) has been reported. However, the underlying mechanisms have not been fully clarified. Thus, this study aimed to investigate the effects of CLA on thermogenesis of interscapular brown adipose tissue (iBAT) and browning of inguinal subcutaneous white adipose tissue (iWAT) and explore the possible signaling pathway. The in vivo results showed that CLA enhanced the O2 consumption and heat production in HFD (high-fat diet)-fed female mice by roughly 38%. Meanwhile, CLA increased the average iBAT temperature by 2°C at the room temperature and cold exposure, respectively. Correspondingly, CLA caused 1.6-and 2.4-fold increases in the expression of UCP1 (uncoupling protein 1) of BAT and iWAT, respectively, suggesting the activated iBAT thermogenesis and iWAT browning in HFD-fed female mice. Meanwhile, CLA could promote the formation of brown and beige adipocytes in differentiated stromal vascular cells (SVCs) isolated from iBAT and iWAT (the expressions of UCP1 were promoted by about twofold changes). In possible mechanisms, CLA stimulated the expression of CD36 and the activation of theAMPK pathway in mice iBAT and iWAT as well as the differentiated SVCs. However, inhibition of CD36 and AMPK (adenosine 5'-monophosphate-activated protein kinase) abolished the promotive effects of CLA on brown and beige adipocytes formation. Hence, we showed that CLA reduced HFD-induced obesity through enhancing iBAT thermogenesis and iWAT browning via theCD36-AMPK pathway.

The Hepatokine Orosomucoid 2 Mediates Beneficial Metabolic Effects of Bile Acids.

Bile acids (BAs) are pleiotropic regulators of metabolism. Elevated levels of hepatic and circulating BAs improve energy metabolism in peripheral organs, but the precise mechanisms underlying the metabolic benefits and harm still need to be fully understood. In the present study, we identified orosomucoid 2 (ORM2) as a liver-secreted hormone (i.e., hepatokine) induced by BAs and investigated its role in BA-induced metabolic improvements in mouse models of dietinduced obesity. Contrary to our expectation, under a high-fat diet (HFD), our Orm2 knockout (Orm2-KO) exhibited a lean phenotype compared to C57BL/6J control, partly due to the increased energy expenditure. However, when challenged with HFD supplemented with cholic acid (HFDCA), Orm2-KO eliminated the anti-obesity effect of BAs, indicating that ORM2 governs BA-induced metabolic improvements. Moreover, hepatic ORM2 overexpression partially replicated BA effects by enhancing insulin sensitivity. Mechanistically, ORM2 suppressed IFNγ/STAT1 activities in inguinal WAT (iWAT) depots, forming the basis for anti-inflammatory effects of BAs and improving glucose homeostasis. In conclusion, our study provides new insights into the molecular mechanisms of BA-induced liver-adipose crosstalk through ORM2 induction.

Ubiquitin ligase RNF20 coordinates sequential adipose thermogenesis with brown and beige fat-specific substrates

In mammals, brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) execute sequential thermogenesis to maintain body temperature during cold stimuli. BAT rapidly generates heat through brown adipocyte activation, and further iWAT gradually stimulates beige fat cell differentiation upon prolonged cold challenges. However, fat depot-specific regulatory mechanisms for thermogenic activation of two fat depots are poorly understood. Here, we demonstrate that E3 ubiquitin ligase RNF20 orchestrates adipose thermogenesis with BAT- and iWAT-specific substrates. Upon cold stimuli, BAT RNF20 is rapidly downregulated, resulting in GABPα protein elevation by controlling protein stability, which stimulates thermogenic gene expression. Accordingly, BAT-specific Rnf20 suppression potentiates BAT thermogenic activity via GABPα upregulation. Moreover, upon prolonged cold stimuli, iWAT RNF20 is gradually upregulated to promote de novo beige adipogenesis. Mechanistically, iWAT RNF20 mediates NCoR1 protein degradation, rather than GABPα, to activate PPARγ. Together, current findings propose fat depot-specific regulatory mechanisms for temporal activation of adipose thermogenesis.

β3-adrenergic receptor methylation mediates fine particulate matter inhalation-impaired white adipose tissue browning

Exposure to fine particulate matter (PM2.5), which contains substantial nanoscale particulate matter, induced metabolic disorder. As a critical organ with the potential for energy expenditure induction, inguinal white adipose tissue (iWAT) browning has hardly been examined with exposure to PM2.5 with nanoparticles. This study aimed to explore the effects of ambient PM2.5 exposure on iWAT browning and the underlying mechanisms to gain a deeper understanding of PM2.5 exposure and metabolic disorders. Based on the characterization of the particulate matter, we observed that PM2.5 exposure impaired iWAT browning, accompanied by inhibition of its oxidative phosphorylation, thermogenesis, and inflammation, which induced an increase in fat mass. Then, PM2.5 exposure induced β3-adrenergic receptor (ADRB3) gene promoter methylation in the iWAT, followed by decreased ADRB3 expression which was negatively correlated with fat mass. Furthermore, ADRB3 agonist, CL316243, elevated ADRB3 expression by inhibiting DNA methylation. Finally, CL316243 treatment corrected the impaired browning capacity and mitochondrial function in the iWAT of mice exposed to PM2.5. Our findings highlight the importance of Adrb3 DNA methylation-mediated iWAT browning impairment in response to PM2.5 exposure and provide a potential therapeutic target for metabolic dysfunction induced by PM2.5 exposure.

Inhibitory effects of naringenin on estrogen deficiency-induced obesity via regulation of mitochondrial dynamics and AMPK activation associated with white adipose tissue browning

AimsPost-ovariectomy (OVX) changes in hormones induce obesity and white adipose tissue (WAT) inflammation. Increased energy expenditure via WAT browning is a novel therapeutic strategy for treating obesity. Naringenin (NAR) reduces inflammation and lipogenesis in obesity and attenuates estrogen deficiency-associated metabolic disorders; however, its role in WAT browning remains unclear. Materials and methodsWe investigated NAR ability to inhibit estrogen deficiency-associated obesity in vivo using a rat model and in vitro using 3T3-L1 adipocytes. Key findingsNAR significantly decreased the body weight and WAT mass of rats. O2 consumption, CO2 production, and energy expenditure were significantly lower in the OVX group than in the sham group, but NAR treatment reversed these effects of OVX. NAR treatment markedly improved glucose intolerance and lipid profiles as well as leptin, adiponectin, and irisin levels. NAR upregulated markers of browning and mitochondrial biogenesis in inguinal WAT. Moreover, it enhanced markers of mitochondrial fusion and inhibited fission via activating the AMP-activated protein kinase pathway. Similar results were observed in 3T3-L1 adipocytes. Moreover, NAR-induced mitochondrial biogenesis and fusion were suppressed by dorsomorphin (an AMP-activated protein kinase inhibitor). SignificanceNAR alleviates obesity and metabolic dysfunction through the induction of WAT browning achieved via the modulation of AMP-activated protein kinase-regulated mitochondrial dynamics in WATs. NAR supplementation may therefore represent a potential intervention for preventing postmenopausal adipose tissue dysregulation.

Metabolic remodeling of visceral and subcutaneous white adipose tissue during reacclimation of rats after cold.

Deciphering lipid metabolism in white adipose tissue (WAT) depots during weight gain is important to understand the heterogeneity of WAT and its roles in obesity. Here, we examined the expression of key enzymes of lipid metabolism and changes in the morphology of representative visceral (epididymal) and subcutaneous (inguinal) WAT (eWAT and iWAT, respectively)-in adult male rats acclimated to cold (4 ± 1°C) for 45 days and reacclimated to room temperature (RT, 22 ± 1°C) for 1, 3, 7, 12, 21, or 45 days. The relative mass of both depots decreased to a similar extent after cold acclimation. However, fatty acid synthase (FAS), glucose-6-phosphate dehydrogenase (G6PDH), and medium-chain acyl-CoA dehydrogenase (ACADM) protein level increased only in eWAT, whereas adipose triglyceride lipase (ATGL) expression increased only in iWAT. During reacclimation, the relative mass of eWAT reached control values on day 12 and that of iWAT on day 45 of reacclimation. The faster recovery of eWAT mass is associated with higher expression of FAS, acetyl-CoA carboxylase (ACC), G6PDH, and ACADM during reacclimation and a delayed increase in ATGL. The absence of an increase in proliferating cell nuclear antigen suggests that the observed depot-specific mass increase is predominantly due to metabolic adjustments. In summary, this study shows a differential rate of visceral and subcutaneous adipose tissue weight regain during post-cold reacclimation of rats at RT. Faster recovery of the visceral WAT as compared to subcutaneous WAT during reacclimation at RT could be attributed to observed differences in the expression patterns of lipid metabolic enzymes.

Remodelling the inguinal adipose sensory system to switch on the furnace: Electroacupuncture stimulation induces brown adipose thermogenesis.

Brown and white adipose tissue mediate thermogenesis through the thermogenetic centre of the brain, but safe methods for activating thermogensis and knowledge of the associated molecular mechanisms are lacking. We investigated body surface electroacupuncture stimulation (ES) at ST25 (targeted at the abdomen) induction of brown adipose thermogenesis and the neural mechanism of this process. Inguinal white adipose tissue (iWAT) and interscapular brown adipose tissue (iBAT) were collected and the thermogenic protein expression levels were measured to evaluate iBAT thermogenesis capacity. The thermogenic centre activating region and sympathetic outflow were evaluated based on neural electrical activity and c-fos expression levels. iWAT sensory axon plasticity was analysed with whole-mount adipose tissue imaging. ES activated the sympathetic nerves in iBAT and the c-fos-positive cells induced sympathetic outflow activation to the iBAT from the medial preoptic area (MPA), the dorsomedial hypothalamus (DM) and the raphe pallidus nucleus (RPA). iWAT denervation mice exhibited decreased c-fos-positive cells in the DM and RPA, and lower recombinant uncoupling orotein 1 peroxisome proliferator-activated receptor, β3-adrenergic receptor, and tyrosine hydroxylase expression. Remodelling the iWAT sensory axons recovered the signal from the MPA to the RPA and induced iBAT thermogenesis. The sympathetic denervation attenuated sensory nerve density. ES induced sympathetic outflow from the thermogenetic centres to iBAT, which mediated thermogenesis. iWAT sensory axon remodelling induced the MPA-DM-RPA-iBAT thermogenesis pathway.

Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis

Coenzyme Q (CoQ) is essential for mitochondrial respiration and required for thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences of CoQ deficiency in specific tissues, such as BAT, remain poorly understood. Here, we show that pharmacological or genetic CoQ deficiency in BAT leads to stress signals causing accumulation of cytosolic mitochondrial RNAs and activation of the eIF2α kinase PKR, resulting in activation of the integrated stress response (ISR) with suppression of UCP1 but induction of FGF21 expression. Strikingly, despite diminished UCP1 levels, BAT CoQ deficiency displays increased whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high-fat diets (HFD). In line with enhanced metabolic rates, BAT and inguinal white adipose tissue (iWAT) interorgan crosstalk caused increased browning of iWAT in BAT-specific CoQ deficient animals. This mitohormesis-like effect depends on the ATF4-FGF21 axis and BAT-secreted FGF21, revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.

Rho-Kinase Is Differentially Expressed in the Adipose Tissue of Rodent and Human in Response to Aging, Sex, and Acute Exercise.

White adipose tissue (WAT) controls energy storage, expenditure, and endocrine function. Rho-kinase (ROCK) is related to impaired thermogenesis, downregulation of preadipocyte differentiation, and adipokine production. Furthermore, WAT ROCK responds to metabolic stress from high-fat diets or diabetes. However, ROCK distribution in adipose depots and its response to aging and sex remain unclear. Thus, we aim to investigate ROCK function in adipose tissue of rodent and human in response to aging and sex. We observed specific differences in the ROCK1/2 distribution in inguinal WAT (ingWAT), perigonadal WAT (pgWAT), and brown adipose tissue of male and female rodents. However, ROCK2 expression was lower in female ingWAT compared with males, a fact that was not observed in the other depots. In the pgWAT and ingWAT of male and female rodents, ROCK activity increased during development. Moreover, middle-aged female rodents and humans showed downregulation in ROCK activity after acute physical exercise. Interestingly, ROCK levels were associated with several inflammatory markers both in rats and humans WAT (Nfkb1, Tnf, Il1b, Il6, and Mcp1). Induction of cell senescence by etoposide elevates ROCK activity in human preadipocytes; however, silencing ROCK1/2 demonstrates improvement in the inflammatory and cell senescence state. Using public databases, several pathways were strongly associated with ROCK modulation in WAT. In summary, WAT ROCK increases with development in association with inflammatory markers. Further, ROCK activity was attenuated by acute physical exercise, implicating it as a possible therapeutic target for metabolism improvement mediated by adipose tissue inflammatory state changes.