Brown Adipose Tissue Lipid Research Articles

A versatile delivery vehicle for cellular oxygen and fuels or metabolic sensor? A review and perspective on the functions of myoglobin.

A canonical view of the primary physiological function of myoglobin (Mb) is that it is an oxygen (O2) storage protein supporting mitochondrial oxidative phosphorylation, especially as the tissue O2 partial pressure (Po2) drops and Mb off-loads O2. Besides O2 storage/transport, recent findings support functions for Mb in lipid trafficking and sequestration, interacting with cellular glycolytic metabolites such as lactate (LAC) and pyruvate (PYR), and "ectopic" expression in some types of cancer cells and in brown adipose tissue (BAT). Data from Mb knockout (Mb-/-) mice and biochemical models suggest additional metabolic roles for Mb, especially regulation of nitric oxide (NO) pools, modulation of BAT bioenergetics, thermogenesis, and lipid storage phenotypes. From these and other findings in the literature over many decades, Mb's function is not confined to delivering O2 in support of oxidative phosphorylation but may serve as an O2 sensor that modulates intracellular Po2- and NO-responsive molecular signaling pathways. This paradigm reflects a fundamental change in how oxidative metabolism and cell regulation are viewed in Mb-expressing cells such as skeletal muscle, heart, brown adipocytes, and select cancer cells. Here, we review historic and emerging views related to the physiological roles for Mb and present working models illustrating the possible importance of interactions between Mb, gases, and small-molecule metabolites in regulation of cell signaling and bioenergetics.

Acetyl-CoA Synthetase Short Chain Family Member-1 (ACSS1) acetylation status is an important regulator of adipose tissue thermogenic function

Brown adipose tissue (BAT) is a crucial regulator of metabolism specialized in dissipating energy in the form of heat. Cold stimulated BAT uses glucose and free fatty acids for thermogenesis, impacting adiposity, glucose control, and insulin sensitivity. Furthermore, the ability of white adipocytes in white adipose tissue (WAT) to transition into thermogenic or beige adipocytes in response to cold exposure or specific pharmacological activators makes them a promising target for developing therapies to address obesity and other metabolic diseases. Sirtuin 3 (SIRT3), an NAD+- dependent deacetylase found within the mitochondria, controls BAT thermogenesis. Loss of SIRT3 in mice results in compromised BAT lipid metabolism, as well as impaired thermoregulation and mitochondrial respiration in BAT, without affecting UCP1 expression and/or function. Acetyl-CoA Synthetase Short Chain Family Member-1 (ACSS1) is an established SIRT3 deacetylation target that synthetizes acetyl-CoA using acetate that is central for fatty acid oxidation (FAO) and mitochondrial metabolism. To understand the function of ACSS1 acetylation role in BAT and WAT during thermogenesis response, we generated a ubiquitous acetylation mimic knock-in mouse by mutating lysine 635 to glutamine (K635Q), previously shown to alter ACSS1 enzymatic activity, which represents a constitutive ACSS1-K635-Ac rendering a protein with altered functionality. Our studies showed that these mice are intolerant to stimulation with b3 adrenergic receptor agonist CL316243 and died within 24 hours. These mice are not able to maintain body temperature and glucose homeostasis and also displayed dysregulated levels of the major lipid synthesis and oxidation pathways in BAT and inguinal subcutaneous WAT (iWAT). Importantly, the CL316243 intolerant phenotype was not observed in Acss1 knock out mice. This data suggests ACSS1-Ac status is an important regulator of adipose cells/tissue thermogenic function, and therefore is a potential therapeutic target for metabolic diseases. These results open a new roadmap to improve metabolic health through post- translational control of ACSS1. Early Stage Investigator Award, Mays Cancer Center P30CA 054174. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Smooth muscle cell-derived Cxcl12 directs macrophage accrual and sympathetic innervation to control thermogenic adipose tissue

Sympathetic innervation of brown adipose tissue (BAT) controls mammalian adaptative thermogenesis. However, the cellular and molecular underpinnings contributing to BAT innervation remain poorly defined. Here, we show that smooth muscle cells (SMCs) support BAT growth, lipid utilization, and thermogenic plasticity. Moreover, we find that BAT SMCs express and control the bioavailability of Cxcl12. SMC deletion of Cxcl12 fosters brown adipocyte lipid accumulation, reduces energy expenditure, and increases susceptibility to diet-induced metabolic dysfunction. Mechanistically, we find that Cxcl12 stimulates CD301+ macrophage recruitment and supports sympathetic neuronal maintenance. Administering recombinant Cxcl12 to obese mice or leptin-deficient (Ob/Ob) mice is sufficient to boost macrophage presence and drive sympathetic innervation to restore BAT morphology and thermogenic responses. Altogether, our data reveal an SMC chemokine-dependent pathway linking immunological infiltration and sympathetic innervation as a rheostat for BAT maintenance and thermogenesis.

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

PurposeThis 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. MethodsFifteen 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). ResultsT2 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. ConclusionsSyMRI can noninvasively evaluate the whitening process of BAT using T2 values and iBAT volume, thereby facilitating the visualization of the whitening process.

80-OR: A New Cytoskeleton-Based Mechanism for Regulating Brown Adipose Tissue Physiology

Human genetic variants in ANK2, encoding the scaffold protein ankyrin-B (AnkB), increase risk for T2D. We characterized the role of AnkB in white adipose tissue (WAT) in mice with AnkB deficiency in both WAT and brown adipose tissue (BAT) (AT-AnkB KO). We found that AnkB loss led to obesity and insulin resistance driven by its role in clathrin mediated endocytosis of GLUT4 in WAT. AT-AnkB KO mice also had lipid accumulation in BAT. However, the cell-autonomous roles of AnkB in BAT and its contribution to energy balance is unknown. To elucidate AnkB’s roles in BAT, we developed mice lacking AnkB in BAT (BAT-AnkB KO). Histology and TEM revealed lipid accumulation in BAT of 4-month-old BAT-AnkB KO mice housed at thermoneutrality. Consistent with this finding, brown adipocytes from AnkB deficient mice also have enlarged lipid droplets, suggesting an AnkB cell-autonomous role in BAT lipid homeostasis. Proteomic-MS revealed that AnkB forms complexes with lipolysis factors Atgl, Hsl and Plin1, and regulators of the PKA pathway, suggesting AnkB plays a role regulating BAT lipolysis. Interestingly, Hsl and Plin1 are elevated in BAT despite the enlarged LDs of BAT-AnkB KO mice, implying either lipolytic deficits or compensatory effects. These findings support RNA sequencing that revealed downregulation of PKA signaling genes, ATPase subunits, and mitochondrial calcium signaling genes in BAT of BAT-AnkB KO mice. Last, peri-droplet mitochondria (PDM), a mitochondria subpopulation with reduced beta-oxidation capacity that contacts LDs, form longer contact sites with BAT LDs from BAT-AnkB KO mice. Together, these findings suggest that early alterations in mitochondrial bioenergetics and lipolysis contribute to BAT LD accumulation. Along with this data, we will present findings on thermogenic regulation in vivo and physiological assays evaluating lipolysis and its major regulators. Disclosure A.Aguillard: None. J.Arricastres: None. J.Tzeng: None. D.Lorenzo: None. Funding American Diabetes Association (1-19-JDF-081 to D.L.); National Science Foundation; Burroughs Wellcome Fund (1022069)

Comparing lipid remodeling of brown adipose tissue, white adipose tissue, and liver after one-week high fat diet intervention with quantitative Raman microscopy.

Brown adipose tissue (BAT) consists of highly metabolically active adipocytes that catabolize nutrients to produce heat. Playing an active role in triacylglycerol (TAG) clearance, research has shown that dietary fatty acids can modulate the TAG chemistry deposition in BAT after weeks-long dietary intervention, similar to what has been shown in white adipose tissue (WAT). Our objective was to compare the influence of sustained, nonchronic dietary intervention (a 1-week interval) on WAT and interscapular BAT lipid metabolism and deposition in situ. We use quantitative, label-free chemical microscopy to show that 1 week of high fat diet (HFD) intervention results in dramatically larger lipid droplet (LD) growth in BAT (and liver) compared to LD growth in inguinal WAT (IWAT). Moreover, BAT showed lipid remodeling as increased unsaturated TAGs in LDs, resembling the dietary lipid composition, while WAT (and liver) did not show lipid remodeling on this time scale. Concurrently, expression of genes involved in lipid metabolism, particularly desaturases, was reduced in BAT and liver from HFD-fed mice after 1 week. Our data show that BAT lipid chemistry remodels exceptionally fast to dietary lipid intervention compared WAT, which further points towards a role in TAG clearance.

640 - MicroRNA-21 overexpression attenuates excess androgen-mediated brown adipose tissue lipid droplet hypertrophy in polycystic ovarian syndrome

640 - MicroRNA-21 overexpression attenuates excess androgen-mediated brown adipose tissue lipid droplet hypertrophy in polycystic ovarian syndrome

Subacute and low dose of tributyltin exposure leads to brown adipose abnormalities in male rats

Tributyltin (TBT) is an obesogenic endocrine disrupting chemical (EDC) linked with several metabolic complications. Brown adipose tissue (BAT) is the principal site for thermogenesis, making it a potential target for obesity management and metabolic disease. However, few studies have evaluated TBT effect on BAT function. In this investigation, we assessed whether subacute (15 days) and low dose of TBT exposure (100 ng/kg/day) results in abnormal BAT morphophysiology in adult male rats. Body temperature, BAT morphology, inflammation, oxidative stress, collagen deposition and BAT metabolic gene expression markers were assessed in room temperature (Room, ∼24 ºC) and after cold tolerance test (Cold, ∼4 ºC) conditions. A reduction in body temperature was observed in both Room and Cold conditions in TBT rats, suggesting abnormal BAT thermogenic function. Changes in BAT morphology were observed in TBT rats, with an increase in BAT lipid accumulation, an increase in BAT unilocular adipocyte number and a decrease in BAT multilocular adipocyte number in Room condition. All these parameters were opposite in Cold condition TBT rats, leading to a borderline increase in BAT UCP1 protein expression. An increase in BAT mast cell number was observed in TBT rats in Room condition. An increase in ED1 protein expression (macrophage marker) was observed in TBT rats in Cold condition. Oxidative stress and collagen deposition increased in both Room and Cold conditions in TBT rats. TBT exposure caused a borderline increase in BAT COL1A1 protein expression in Cold condition. Further, strong negative correlations were observed between body temperature and BAT lipid accumulation, and BAT lipid accumulation and multilocular adipocyte number. Thus, these data suggest that TBT exposure impaired BAT morphophysiology through impacts on lipid accumulation, inflammation, fibrosis and oxidative stress in male rats.

Isolation and Mass Spectrometry-Based Profiling of Major Lipids in Brown Adipose Tissue.

Brown adipose tissue (BAT) is an important regulator of metabolic homeostasis through its role in adaptive thermogenesis and control of whole-body glucose metabolism. Lipids play multiple roles in BAT functions, including serving as a fuel source for thermogenesis, mediating inter-organelle cross talk, and acting as BAT-derived signaling molecules that influence systemic energy metabolism. Profiling of various lipids in BAT under distinct metabolic states could provide new insights into their roles in the biology of the thermogenic fat. In this chapter, we describe a step-by-step workflow starting from sample preparations to mass spectrometry-based analysis of fatty acids and phospholipids in BAT.

Balanced control of thermogenesis by nuclear receptor corepressors in brown adipose tissue

Brown adipose tissue (BAT) is a key thermogenic organ whose expression of uncoupling protein 1 (UCP1) and ability to maintain body temperature in response to acute cold exposure require histone deacetylase 3 (HDAC3). HDAC3 exists in tight association with nuclear receptor corepressors (NCoRs) NCoR1 and NCoR2 (also known as silencing mediator of retinoid and thyroid receptors [SMRT]), but the functions of NCoR1/2 in BAT have not been established. Here we report that as expected, genetic loss of NCoR1/2 in BAT (NCoR1/2 BAT-dKO) leads to loss of HDAC3 activity. In addition, HDAC3 is no longer bound at its physiological genomic sites in the absence of NCoR1/2, leading to a shared deregulation of BAT lipid metabolism between NCoR1/2 BAT-dKO and HDAC3 BAT-KO mice. Despite these commonalities, loss of NCoR1/2 in BAT does not phenocopy the cold sensitivity observed in HDAC3 BAT-KO, nor does loss of either corepressor alone. Instead, BAT lacking NCoR1/2 is inflamed, particularly with respect to the interleukin-17 axis that increases thermogenic capacity by enhancing innervation. Integration of BAT RNA sequencing and chromatin immunoprecipitation sequencing data revealed that NCoR1/2 directly regulate Mmp9, which integrates extracellular matrix remodeling and inflammation. These findings reveal pleiotropic functions of the NCoR/HDAC3 corepressor complex in BAT, such that HDAC3-independent suppression of BAT inflammation counterbalances stimulation of HDAC3 activity in the control of thermogenesis.

The conserved Mediator subunit cyclin C (CCNC) is required for brown adipocyte development and lipid accumulation

ObjectiveCyclin C (CCNC) is the most conserved subunit of the Mediator complex, which is an important transcription cofactor. Recently, we have found that CCNC facilitates brown adipogenesis in vitro by activating C/EBPα-dependent transcription. However, the role of CCNC in brown adipose tissue (BAT) in vivo remains unclear. MethodsWe generated conditional knock-out mice by crossing Ccncflox/flox mice with Myf5Cre, Ucp1Cre or AdipoqCre transgenic mice to investigate the role of CCNC in BAT development and function. We applied glucose and insulin tolerance test, cold exposure and indirect calorimetry to capture the physiological phenotypes and used immunostaining, immunoblotting, qRT-PCR, RNA-seq and cell culture to elucidate the underlying mechanisms. ResultsHere, we show that deletion of CCNC in Myf5+ progenitor cells caused BAT paucity, despite the fact that there was significant neonatal lethality. Mechanistically different from in vitro, CCNC deficiency impaired the proliferation of embryonic brown fat progenitor cells without affecting brown adipogenesis or cell death. Interestingly, CCNC deficiency robustly reduced age-dependent lipid accumulation in differentiated brown adipocytes in all three mouse models. Mechanistically, CCNC in brown adipocytes is required for lipogenic gene expression through the activation of the C/EBPα/GLUT4/ChREBP axis. Consistent with the importance of de novo lipogenesis under carbohydrate-rich diets, high-fat diet (HFD) feeding abolished CCNC deficiency -caused defects of lipid accumulation in BAT. Although insulin sensitivity and response to acute cold exposure were not affected, CCNC deficiency in Ucp1+ cells enhanced the browning of white adipose tissue (beiging) upon prolonged cold exposure. ConclusionsTogether, these data indicate an important role of CCNC-Mediator in the regulation of BAT development and lipid accumulation in brown adipocytes.

Supplementation of diet with Brazil nut modulates body composition, bone parameters, and lipid peroxidation in Wistar rats.

Oxidative stress, adipose tissue, and bone compartments can be disturbed in chronic diseases. Non-pharmacological strategies, such as Brazil nuts (BNs), can improve these parameters. This study evaluated the effects of BN supplementation at different concentrations on body composition, lipid profile, and peroxidation in healthy rats. Male Wistar rats were divided into three groups: control (CT), Brazil nut 5% (BN5), and Brazil nut 10% (BN10) groups. Body composition, brown adipose tissue (BAT), plasma lipid peroxidation, and lipid profile were evaluated in the three groups. The BN5 group showed an improvement in all bone parameters compared with that of the CT group (p <.0001). The BN5 and BN10 groups showed reduced plasma lipid peroxidation compared with that of the CT group (p=.0009), whereas the BN10 group presented lower BAT lipid peroxidation than that of the other groups (p=.01). High-density lipoprotein-cholesterol (HDL-c) levels were higher in the BN5 group than in the CT group (p=.01). Conclusively, the use of BNs in a controlled manner promoted improvement in bone parameters, HDL-c levels, and lipid peroxidation in healthy rats. PRACTICAL APPLICATIONS: Nuts has been included in the diet because of their versatility, acceptance, and easy access. Among them, Brazil nut (BN) is considered one of the major known food sources of selenium as well as a source of fibers, unsaturated fatty acids, and phenolic compounds. Studies have shown that BN supplementation is effective in reducing oxidative stress, inflammation, lipid peroxidation, and selenium deficiency when used as a non-pharmacological strategy in experimental models of chronic diseases and in clinical trials. The present study showed that controlled administration of BN improved bone parameters, high-density lipoprotein-cholesterol levels, and lipid peroxidation in healthy rats. Therefore, BN is a promising non-pharmacological agent for the prevention of the onset of chronic non-communicable diseases.

Role of Endothelial Cell Lipoprotein Lipase for Brown Adipose Tissue Lipid and Glucose Handling.

Cold-induced activation of brown adipose tissue (BAT) has an important impact on systemic lipoprotein metabolism by accelerating the processing of circulating triglyceride-rich lipoproteins (TRL). Lipoprotein lipase (LPL) expressed by adipocytes is translocated via endothelial to the capillary lumen, where LPL acts as the central enzyme for the vascular lipoprotein processing. Based on preliminary data showing that LPL is not only expressed in adipocytes but also in endothelial cells of cold-activated BAT, we aimed to dissect the relevance of endothelial versus adipocyte LPL for lipid and energy metabolism in the context of adaptive thermogenesis. By metabolic studies we found that cold-induced triglyceride uptake into BAT, lipoprotein disposal, glucose uptake and adaptive thermogenesis were not impaired in mice lacking Lpl exclusively in endothelial cells. This finding may be explained by a compensatory upregulation in the expression of adipocyte-derived Lpl and endothelial lipase (Lipg).

Fructose consumption induces molecular adaptations involving thyroid function and thyroid-related genes in brown adipose tissue in rats.

The increasing incidence of metabolic diseases is in part due to the high fructose consumption, a carbohydrate vastly used in industry, with a potent lipogenic capacity. Thyroid hormones (TH) are essential for metabolism regulation and are associated with changes in body weight, energy expenditure, insulin sensitivity, and dyslipidemia. This study aimed to investigate the influence of fructose intake on thyroid function and thyroid-related genes. Male Wistar rats were divided into Control (CT, n=8) and Fructose (FT - 10% in drinking water, n=8) groups for three weeks. The FT group showed higher glycemia and serum triacylglycerol, indicating metabolic disturbances, and increased thyroid mass, accompanied by higher expression of Srebf1c and Lpl, suggesting increased lipid synthesis. The FT group also presented higher expression of Tpo and Dio1 in the thyroid, suggesting activation of the thyroid gland, but with no alterations in serum TH concentrations. Brown adipose tissue (BAT) of the FT group exhibited higher expression of Dio2, Thra, and Thrb, indicating increased T3 intra-tissue bioavailability and signaling. These responses were accompanied by increased BAT mass and higher expression of Adrb3, Pparg, Srebf1c, Fasn, Ppara, and Ucp1, suggesting increased BAT adrenergic sensitivity, lipid synthesis, oxidation, and thermogenesis. Therefore, short-term fructose consumption induced thyroid molecular alterations and increased BAT expression of thyroid hormone-related signaling genes that potentially contributed to higher BAT activity.

Testosterone reduces metabolic brown fat activity in male mice.

Brown adipose tissue (BAT) burns substantial amounts of mainly lipids to produce heat. Some studies indicate that BAT activity and core body temperature are lower in males than females. Here we investigated the role of testosterone and its receptor (the androgen receptor; AR) in metabolic BAT activity in male mice. Castration, which renders mice testosterone deficient, slightly promoted the expression of thermogenic markers in BAT, decreased BAT lipid content, and increased basal lipolysis in isolated brown adipocytes. Further, castration increased the core body temperature. Triglyceride-derived fatty acid uptake, a proxy for metabolic BAT activity in vivo, was strongly increased in BAT from castrated mice (4.5-fold increase vs sham-castrated mice) and testosterone replacement reversed the castration-induced increase in metabolic BAT activity. BAT-specific AR deficiency did not mimic the castration effects in vivo and AR agonist treatment did not diminish the activity of cultured brown adipocytes in vitro, suggesting that androgens do not modulate BAT activity via a direct, AR-mediated pathway. In conclusion, testosterone is a negative regulator of metabolic BAT activity in male mice. Our findings provide new insight into the metabolic actions of testosterone.

Mig-6 is essential for glucose homeostasis and thermogenesis in brown adipose tissue

Brown adipose tissue (BAT) is an anti-obese and anti-diabetic tissue that stimulates energy expenditure in the form of adaptive thermogenesis through uncoupling protein 1 (UCP1). Mitogen-inducible gene-6 (Mig-6) is a negative regulator of epidermal growth factor receptor (EGFR) that interacts with many cellular partners and has multiple cellular functions. We have recently reported that Mig-6 is associated with diabetes and metabolic syndrome. However, its function in BAT is unknown. We generated a brown adipocyte-specific Mig-6 knock-in mouse (BKI) to examine the role of Mig-6 in BAT. Mig-6 BKI mice had improved glucose tolerance on a normal chow diet. Mig-6 BKI mice also revealed activated thermogenesis and the size of the BAT lipid droplets was reduced. Additionally, Mig-6 regulated cAMP-PKA signaling-induced UCP1 expression in brown adipocytes. Taken together, these results demonstrate that Mig-6 affects glucose tolerance and thermogenesis in BAT.

A BAFF/APRIL axis regulates obesogenic diet-driven weight gain

The impact of immune mediators on weight homeostasis remains underdefined. Interrogation of resistance to diet-induced obesity in mice lacking a negative regulator of Toll-like receptor signaling serendipitously uncovered a role for B cell activating factor (BAFF). Here we show that overexpression of BAFF in multiple mouse models associates with protection from weight gain, approximating a log-linear dose response relation to BAFF concentrations. Gene expression analysis of BAFF-stimulated subcutaneous white adipocytes unveils upregulation of lipid metabolism pathways, with BAFF inducing white adipose tissue (WAT) lipolysis. Brown adipose tissue (BAT) from BAFF-overexpressing mice exhibits increased Ucp1 expression and BAFF promotes brown adipocyte respiration and in vivo energy expenditure. A proliferation-inducing ligand (APRIL), a BAFF homolog, similarly modulates WAT and BAT lipid handling. Genetic deletion of both BAFF and APRIL augments diet-induced obesity. Lastly, BAFF/APRIL effects are conserved in human adipocytes and higher BAFF/APRIL levels correlate with greater BMI decrease after bariatric surgery. Together, the BAFF/APRIL axis is a multifaceted immune regulator of weight gain and adipose tissue function.

Changes in brown adipose tissue lipid mediator signatures with aging, obesity, and DHA supplementation in female mice.

Brown adipose tissue (BAT) dysfunction in aging and obesity has been related to chronic unresolved inflammation, which could be mediated by an impaired production of specialized proresolving lipid mediators (SPMs), such as Lipoxins-LXs, Resolvins-Rvs, Protectins-PDs, and Maresins-MaRs. Our aim was to characterize the changes in BAT SPMs signatures and their association with BAT dysfunction during aging, especially under obesogenic conditions, and their modulation by a docosahexaenoic acid (DHA)-rich diet. Lipidomic, functional, and molecular studies were performed in BAT of 2- and 18-month-old lean (CT) female mice and in 18-month-old diet-induced obese (DIO) mice fed with a high-fat diet (HFD), or a DHA-enriched HFD. Aging downregulated Prdm16 and UCP1 levels, especially in DIO mice, while DHA partially restored them. Arachidonic acid (AA)-derived LXs and DHA-derived MaRs and PDs were the most abundant SPMs in BAT of young CT mice. Interestingly, the sum of LXs and of PDs were significantly lower in aged DIO mice compared to young CT mice. Some of the SPMs most significantly reduced in obese-aged mice included LXB4 , MaR2, 4S,14S-diHDHA, 10S,17S-diHDHA (a.k.a. PDX), and RvD6. In contrast, DHA increased DHA-derived SPMs, without modifying LXs. However, MicroPET studies showed that DHA was not able to counteract the impaired cold exposure response in BAT of obese-aged mice. Our data suggest that a defective SPMs production could underlie the decrease of BAT activity observed in obese-aged mice, and highlight the relevance to further characterize the physiological role and therapeutic potential of specific SPMs on BAT development and function.

Disruption of Adipose Tissue Metabolism by Glucocorticoids Is Attenuated With LXRβ Antagonism

Excessive exposure to glucocorticoids (GCs), either from endogenous overproduction of cortisol, or exogenous pharmacological GC treatment, potentiates the development of diabetes and obesity in a fat depot-specific manner. Undesirable metabolic side effects resulting from the activation of the glucocorticoid receptor (GR) remain a key limitation to the long-term therapeutic use of GCs as immunosuppressants. GC treatment disrupts the thermogenic function of brown adipose tissue (BAT) and enhances futile cycling within white adipose tissue (WAT). Mice lacking the liver X receptors (LXRs) were previously shown to have smaller AT depots with enhanced BAT activity compared to wildtype (WT) mice. We previously demonstrated that LXRβ is required to mediate the side effects of GCs in the liver but not the beneficial anti-inflammatory effects of GCs. The discovery of this GC/LXRβ cross-talk led to the hypothesis that LXRβ antagonism may be therapeutically beneficial to prevent GC-induced dysfunction in AT. To test this idea, LXRα-/- mice were treated for 5 days with vehicle, 5 mg/kg dexamethasone (Dex, a synthetic GC agonist), and/or 40 mg/kg GSK2033 (GSK, non-selective LXR antagonist). As expected, Dex-treated mice showed significant accumulation of lipids in BAT and were unable to maintain their body temperature when exposed to cold, yet GSK was able to protect against these effects. Dex increased body fat mass and caused adipocyte enlargement in WAT which was not observed in mice co-treated with GSK. At the transcriptional level, GSK attenuated Dex-mediated downregulation of thermogenic genes in BAT, and upregulation of lipogenic genes in WAT. Similar beneficial changes were confirmed in WT mice. The protection afforded by GSK against Dex-induced fat accumulation was confirmed to be cell-autonomous from studies in adipose-specific LXRβ-/- mice (AdβKO). Dex-dependent increases in lipolysis in gonadal WAT and plasma free fatty acids (FFA) were also attenuated by GSK co-treatment. With GSK co-treatment, Dex-induced liver steatosis was diminished suggesting that LXRβ antagonism attenuated FFA shuttling to the liver. The lipolytic and lipotoxic effects of Dex in AT and liver were largely abrogated in AdβKO along with improved systemic insulin sensitivity. Overall, our data suggest that LXRβ antagonism prevents disruption of BAT and WAT (and indirectly liver) function caused by GC treatment in an in vivo model, highlighting the potential role of LXRβ antagonists in combating the negative effects of excessive GC exposure on the development of diabetes and obesity. The identification of this novel mechanism of interrupting GC adipose tissue action suggests therapeutic targeting of LXRβ with an antagonist could improve the health of patients currently taking GCs to control inflammation but suffer the detrimental side effects of drug treatment.

Effect of 4-week electroacupuncture intervention on "Browning" of white fat in rats and its mechanism

Objective: To investigate the effects of 4-week electroacupuncture intervention on "Browning" of white fat in rats, and to explore its molecular mechanisms. Methods: Twenty-four 8-week-old male SD rats were randomly divided into sedentary group (Sed), aerobic exercise group (Exe) and electroacupuncture group (ElA), 8 rats in each group. Exe group used 65% Max oxygen uptake intensity treadmill exercise, 1 h/d,6 d/w, while the ElA group used electric acupuncture to stimulate "zusanli" and "tianshu" points, 20 min/d,6 d/w, and the weight of rats was recorded every week. After 4 weeks of intervention, blood samples were collected from the apex and abdominal aorta. The wet weight of scapular fat and perirenal fat of rats was detected and the body fat and the serum levels of Irisin were determined. What's more, the expressions of adenosine 5'-monophosphate activated protein kinase-α (AMPKα), phosphorylation of adenosine 5'-monophosphate activated protein kinase-α (p-AMPKα), peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α), fibronectin type III domain containing 5 (FNDC5) and uncoupling protein (UCP1) and brown adipose tissue lipid droplets in rats were detected. Results: Compared with the Sed group, the weight gain of rats in the Exe and ElA groups was decreased significantly from the second week. After 4 weeks, the body weight and body fat of the Exe and ElA groups were decreased significantly (P＜0.01), while there was no significant difference between the Exe and ElA groups (P＞0.05). ②After 4 weeks of intervention, the white fat wet weight of ElA group and Exe group was significantly was reduced (P＜0.05 or P＜0.01). ③The serum levels of Irisin in Exe and ElA groups were significantly increased (P＜0.05), and the expressions of p-AMPKα/AMPKα, PGC-1α, FNDC5 in the gastrocnemius and the expressions of UCP1 in white fat and brown adipose tissue of Exe and ElA groups were increased (P＜0.05). ④The area of lipid droplets in white and brown adipose tissue of Exe and ElA groups was significantly reduced (P＜ 0.01). Conclusion: 4 weeks of electroacupuncture intervention can effectively control the weight of rats and induce "browning" of white fat, and its effect was similar to aerobic exercise, which may be release Irisin through the AMPKα-PGC-1α-FNDC5-Irisin signaling pathway, and then "crosstalk" with adipose tissue, up-regulate the expression of UCP1, and induce "browning" of white adipose tissue.