White Adipose Tissue Research Articles

Erythropoietin regulates energy metabolism through EPO-EpoR-RUNX1 axis

Erythropoietin (EPO) plays a key role in energy metabolism, with EPO receptor (EpoR) expression in white adipose tissue (WAT) mediating its metabolic activity. Here, we show that male mice lacking EpoR in adipose tissue exhibit increased fat mass and susceptibility to diet-induced obesity. Our findings indicate that EpoR is present in WAT, brown adipose tissue, and skeletal muscle. Elevated EPO in male mice improves glucose tolerance and insulin sensitivity while reducing expression of lipogenic-associated genes in WAT, which is linked to an increase in transcription factor RUNX1 that directly inhibits lipogenic genes expression. EPO treatment in wild-type male mice decreases fat mass and lipogenic gene expression and increase in RUNX1 protein in adipose tissue which is not observed in adipose tissue EpoR ablation mice. EPO treatment decreases WAT ubiquitin ligase FBXW7 expression and increases RUNX1 stability, providing evidence that EPO regulates energy metabolism in male mice through the EPO-EpoR-RUNX1 axis.

Calenduloside E Ameliorates Inflammatory Responses in Adipose Tissue via Sirtuin 2-NLRP3 Inflammasome Axis.

Obesity-related metabolic diseases are associated with a chronic inflammatory state. Calenduloside E (CE) is a triterpene saponin from sugar beet. In mouse models, CE reduced pro-inflammatory cytokines in white adipose tissue (WAT) and decreased macrophage infiltration of WAT. And CE inhibited pyroptosis in J774A.1 cells and WAT by inhibiting the activation of the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome. Moreover, CE could trigger the activation of Sirtuin 2 (SIRT2), leading to a decrease in the acetylation of NLRP3, particularly at the K24 site. In addition, it has been shown that CE can reduce inflammation in adipocytes that have been induced by macrophage-conditioned medium. However, the selective SIRT2 inhibitor AGK2 hindered the beneficial effects of CE. In summary, CE has the capacity to impede NLRP3-mediated pyroptosis by triggering SIRT2 activity, thus positioning CE as a promising therapeutic avenue for combating obesity-related metabolic disorders.

Influence of different types of dietary sugars on the intestinal mucosa and hepatic lipid metabolism in germ-free mice

The excessive consumption of dietary sugar induces changes in gut microbiota, which is associated with obesity and metabolic dysregulation. This study investigated the effects of monosaccharide and fructooligosaccharide (FOS) intake on metabolic function and intestinal environment in germ-free (GF) mice lacking gut microbiota. GF mice were provided with a chow diet and administered a water solution containing 15 % glucose, fructose, or FOS for 4 weeks. Compared with FOS, glucose, and fructose induced increased hepatic lipid accumulation, increased adipocyte size in white adipose tissue, and upregulated hepatic lipogenic gene expression. FOS exhibited notably higher activation of hepatic AMP-activated protein kinase compared with those consuming glucose or fructose. Moreover, the number of goblet cells in the intestinal mucosa increased significantly with FOS consumption. Collectively, these findings indicate that while monosaccharides caused metabolic disorders in GF mice, FOS alleviated these disorders and increased the number of goblet cells in the intestinal mucosa. These results provide evidence for the occurrence of these effects independently of the gut microbiota.

The role of intestinal microbiota in physiologic and body compositional changes that accompany CLA-mediated weight loss in obese mice

ObjectiveObesity continues to be a major problem, despite known treatment strategies such as lifestyle modifications, pharmaceuticals, and surgical options, necessitating the development of novel weight loss approaches. The naturally occurring fatty acid, 10,12 conjugated linoleic acid (10,12 CLA), promotes weight loss by increasing fat oxidation and browning of white adipose tissue, leading to increased energy expenditure in obese mice. Coincident with weight loss, 10,12 CLA also alters the murine gut microbiota by enriching for microbes that produce short chain fatty acids (SCFAs), with concurrent elevations in fecal butyrate and plasma acetate. MethodsTo determine if the observed microbiota changes are required for 10,12 CLA-mediated weight loss, adult male mice with diet-induced obesity were given broad-spectrum antibiotics (ABX) to perturb the microbiota prior to and during 10,12 CLA-mediated weight loss. Conversely, to determine whether gut microbes were sufficient to induce weight loss, conventionally-raised and germ-free mice were transplanted with cecal contents from mice that had undergone weight loss by 10,12 CLA supplementation. ResultsWhile body weight was minimally modulated by ABX-mediated perturbation of gut bacterial populations, adult male mice given ABX were more resistant to the increased energy expenditure and fat loss that are induced by 10,12 CLA supplementation. Transplanting cecal contents from donor mice losing weight due to oral 10,12 CLA consumption into conventional or germ-free mice led to improved glucose metabolism with increased butyrate production. ConclusionsThese data suggest a critical role for the microbiota in diet-modulated changes in energy balance and glucose metabolism, and distinguish the metabolic effects of orally delivered 10,12 CLA from cecal transplantation of the resulting microbiota.

Accelerated BDNF expression in visceral white adipose tissues following high-fat diet feeding in mice.

Brain-derived neurotrophic factor (BDNF) is expressed in the white adipose tissues (WATs), and the expression increases during high-fat diet (HFD) feeding, implicating its role in obesity. Here, we focused on BDNF expression in epididymal WAT (eWAT), a visceral adipose tissue, in mice. During 2 weeks of HFD feeding, Bdnf mRNA expression in eWAT slightly increased, but a robust increase was observed after 8 weeks of HFD feeding. This upregulation of Bdnf mRNA was correlated with significant induction of hypoxia-inducible factor 1α (Hif1α) and platelet-derived growth factor subunit B (Pdgfb) mRNA in eWAT following 8 weeks of HFD feeding. Furthermore, the increased expression of the M1 macrophage markers was strongly correlated with the elevation of Bdnf mRNA in the eWAT. Notably, 8 weeks of HFD feeding significantly elevated Tnfα mRNA expression in eWAT, while no such induction was observed in inguinal WAT (iWAT). In contrast, the expression of Adipoq (adiponectin), implicated in improved insulin sensitivity and anti-inflammatory effects, was significantly upregulated in iWAT, but not in eWAT. Thus, our study may show the role of BDNF in eWAT in obesity models, potentially contributing to the pathological state of visceral adipose tissues.

Loss of HD-PTP function results in lipodystrophy, defective cellular signaling and altered lipid homeostasis.

His domain protein tyrosine phosphatase (HD-PTP; also known as PTPN23) facilitates function of the endosomal sorting complexes required for transport (ESCRTs) during multivesicular body (MVB) formation. To uncover its role in physiological homeostasis, embryonic lethality caused by a complete lack of HD-PTP was bypassed through generation of hypomorphic mice expressing reduced protein, resulting in animals that are viable into adulthood. These mice exhibited marked lipodystrophy and decreased receptor-mediated signaling within white adipose tissue (WAT), involving multiple prominent pathways including RAS/MAPK, phosphoinositide 3-kinase (PI3K)/AKT and receptor tyrosine kinases (RTKs), such as EGFR. EGFR signaling was dissected in vitro to assess the nature of defective signaling, revealing decreased trans-autophosphorylation and downstream effector activation, despite normal EGF binding. This corresponds to decreased plasma membrane cholesterol and increased lysosomal cholesterol, likely resulting from defective endosomal maturation necessary for cholesterol trafficking and homeostasis. The ESCRT components Vps4 and Hrs have previously been implicated in cholesterol homeostasis; thus, these findings expand knowledge on which ESCRT subunits are involved in cholesterol homeostasis and highlight a non-canonical role for HD-PTP in signal regulation and adipose tissue homeostasis.

Abstract B002: Tumor-secreted PTHrP facilitates pancreatic cancer cachexia by regulation of de novo lipogenesis pathway

Abstract Pancreatic cancer is associated with one of the highest and most severe forms of cancer- associated cachexia amongst solid tumors. In an effort to further our understanding of the molecular etiology of pancreatic cancer-associated cachexia, we have developed mouse models to study adipose tissue wasting during Pancreatic Ductal Adenocarcinoma (PDAC) progression. In these pursuits, we have identified a pro-cachectic factor, PTHrP, that is produced and secreted by PDAC tumor cells and directly signals to adipocytes to facilitate wasting. Genetic deletion and pharmacological inhibition of PTHrP significantly extended the survival of tumor-bearing animals and dramatically reduced cachectic phenotypes in these animals, manifesting as decreased adipose and muscle tissue wasting. Mechanistic studies have shown crosstalk between tumor-cell derived PTHrP and adipose tissue PTH1R that drives the cachectic phenotype. Finally, bulk RNA sequencing analysis in PTHrP-driven cachectic models point towards a role for reduced de novo lipogenesis and adipogenesis in cachectic adipose depots, suggesting potential rewiring of the metabolic profile of white adipose tissue in tumor-bearing mice with higher PTHrP expression. Citation Format: Nikita Bhalerao, Jessica Peura, Yamini Ogoti, Calvin Johnson, Qingbo Chen, Ekaterina Korobkina, Faith Keller, Maximillan Wengyn, Robert Norgard, Richard Kremmer, Emma Watson, Marcus Ruscetti, David Guertin, Jason R Pitarresi. Tumor-secreted PTHrP facilitates pancreatic cancer cachexia by regulation of de novo lipogenesis pathway [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B002.

Lycium barbarum polysaccharide increases thermogenesis and energy metabolism through modulation of the gut microbiota to confer resistance to cold temperatures.

Traditional Chinese medical literature contains numerous records of many traditional Chinese herbal medicines that exhibit efficacy in enhancing resistance to cold, yet there is a lack of scientific explanation. Lycium barbarum is among the herbal medicines that are explicitly documented to enhance resistance to cold in the "Ben Cao Gang Mu (Compendium of Materia Medica)". Herein, we investigated L. barbarum polysaccharide (LBP)-induced browning of inguinal white adipose tissue (iWAT), energy expenditure and thermogenic function in a long-term (4 months) treatment mouse model. LBP supplementation resulted in a significant reduction in weight and adipocyte size in iWAT, along with increased gut microbiota diversity. Specifically, the levels of Lachnospiraceae, Ruminococcaceae and Bacteroidaceae (short-chain fatty acid-producing bacteria) were elevated, leading to a higher level of short-chain fatty acids (SCFAs) in the caecal content. These effects subsequently triggered the release of glucagon-like peptide-1 (GLP-1) and activated the CREB/PGC1α signaling pathway in iWAT, thereby increasing energy expenditure and enhancing thermogenic function. The antibiotic treatment experiments confirmed that the LBP-mediated gut microbiota participated in the process of iWAT browning. In summary, our findings provide the first scientific explanation and mechanistic insights into the cold resistance of L. barbarum and identify potentially safe natural product supplements for individuals in alpine areas.

Effects of Omega-3 Polyunsaturated Fatty Acids on the Formation of Adipokines, Cytokines, and Oxylipins in Retroperitoneal Adi-Pose Tissue of Mice.

Oxylipins and specialized pro-resolving lipid mediators (SPMs) derived from polyunsaturated fatty acids (PUFAs) are mediators that coordinate an active process of inflammation resolution. While these mediators have potential as circulating biomarkers for several disease states with inflammatory components, the source of plasma oxylipins/SPMs remains a matter of debate but may involve white adipose tissue (WAT). Here, we aimed to investigate to what extent high or low omega (n)-3 PUFA enrichment affects the production of cytokines and adipokines (RT-PCR), as well as oxylipins/SPMs (liquid chromatography-tandem mass spectrometry) in the WAT of mice during lipopolysaccharide (LPS)-induced systemic inflammation (intraperitoneal injection, 2.5 mg/kg, 24 h). For this purpose, n-3 PUFA genetically enriched mice (FAT-1), which endogenously synthesize n-3 PUFAs, were compared to wild-type mice (WT) and combined with n-3 PUFA-sufficient or deficient diets. LPS-induced systemic inflammation resulted in the decreased expression of most adipokines and interleukin-6 in WAT, whereas the n-3-sufficient diet increased them compared to the deficient diet. The n-6 PUFA arachidonic acid was decreased in WAT of FAT-1 mice, while n-3 derived PUFAs (eicosapentaenoic acid, docosahexaenoic acid) and their metabolites (oxylipins/SPMs) were increased in WAT by genetic and nutritional n-3 enrichment. Several oxylipins/SPMs were increased by LPS treatment in WAT compared to PBS-treated controls in genetically n-3 enriched FAT-1 mice. Overall, we show that WAT may significantly contribute to circulating oxylipin production. Moreover, n-3-sufficient or n-3-deficient diets alter adipokine production. The precise interplay between cytokines, adipokines, and oxylipins remains to be further investigated.

Reversing Pdgfrβ signaling restores metabolically active beige adipocytes by alleviating ILC2 suppression in aged and obese mice

ObjectivePlatelet Derived Growth Factor Receptor Beta (Pdgfrβ) suppresses the formation of cold temperature-induced beige adipocytes in aged mammals. We aimed to determine if deleting Pdgfrβ in aged mice could rejuvenate metabolically active beige adipocytes by activating group 2 innate lymphoid cells (ILC2), and whether this effect could counteract diet-induced obesity-associated beige fat decline. MethodsWe employed Pdgfrβ gain-of-function and loss-of-function mouse models targeting beige adipocyte progenitor cells (APCs). Our approach included cold exposure, metabolic cage analysis, and age and diet-induced obesity models to examine beige fat development and metabolic function under varied Pdgfrβ activity. ResultsAcute cold exposure alone enhanced metabolic benefits in aged mice, irrespective of beige fat generation. However, Pdgfrβ deletion in aged mice reestablished the formation of metabolically functional beige adipocytes, enhancing metabolism. Conversely, constitutive Pdgfrβ activation in young mice stymied beige fat development. Mechanistically, Pdgfrβ deletion upregulated IL-33, promoting ILC2 recruitment and activation, whereas Pdgfrβ activation reduced IL-33 levels and suppressed ILC2 activity. Notably, diet-induced obesity markedly increased Pdgfrβ expression and Stat1 signaling, which inhibited IL-33 induction and ILC2 activation. Genetic deletion of Pdgfrβ restored beige fat formation in obese mice, improving whole-body metabolism. ConclusionsThis study reveals that cold temperature exposure alone can trigger metabolic activation in aged mammals. However, reversing Pdgfrβ signaling in aged and obese mice not only restores beige fat formation but also renews metabolic function and enhances the immunological environment of white adipose tissue (WAT). These findings highlight Pdgfrβ as a crucial target for therapeutic strategies aimed at combating age- and obesity-related metabolic decline.

The Therapeutic Potential of Theobromine in Obesity: A Comprehensive Review.

Obesity, characterized by chronic low-grade inflammation, is a significant health concern. Phytochemicals found in plants are being explored for therapeutic use, particularly in combating obesity. Among these, theobromine, commonly found in cocoa and chocolate, shows promise. Although not as extensively studied as caffeine, theobromine exhibits positive effects on human health. It improves lipid profiles, aids in asthma treatment, lowers blood pressure, regulates gut microbiota, reduces tumor formation, moderates blood glucose levels, and acts as a neuroprotective agent. Studies demonstrate its anti-obesity effects through mechanisms such as browning of white adipose tissue, activation of brown adipose tissue, anti-inflammatory properties, and reduction of oxidative stress. This study aims to suggest theobromine as a potential therapeutic agent against obesity-related complications.

Chronic intermittent hypoxia triggers cardiac fibrosis: Role of epididymal white adipose tissue senescent remodeling?

Obstructive sleep apnea (OSA) is a growing health problem affecting nearly 1 billion people worldwide. The landmark feature of OSA is chronic intermittent hypoxia (CIH), accounting for multiple organ damage, including heart disease. CIH profoundly alters both visceral white adipose tissue (WAT) and heart structure and function, but little is known regarding inter-organ interaction in the context of CIH. We recently showed that visceral WAT senescence drives myocardial alterations in aged mice without CIH. Here, we aimed at investigating whether CIH induces a premature visceral WAT senescent phenotype, triggering subsequent cardiac remodeling. In a first experiment, 10-week-old C57bl6J male mice (n = 10/group) were exposed to 14 days of CIH (8 h daily, 5%-21% cyclic inspired oxygen fraction, 60 s per cycle). In a second series, mice were submitted to either epididymal WAT surgical lipectomy or sham surgery before CIH exposure. Finally, we used p53 deficient mice or Wild-type (WT) littermates, also exposed to the same CIH protocol. Epididymal WAT was assessed for fibrosis, DNA damages, oxidative stress, markers of senescence (p16, p21, and p53), and inflammation by RT-qPCR and histology, and myocardium was assessed for fibrosis and cardiomyocyte hypertrophy. CIH-induced epididymal WAT remodeling characterized by increased fibrosis, oxidative stress, DNA damage response, inflammation, and increased expression of senescent markers. CIH-induced epididymal WAT remodeling was associated with subtle and early myocardial interstitial fibrosis. Both epididymal WAT surgical lipectomy and p53 deletion prevented CIH-induced myocardial fibrosis. Short-term exposure to CIH induces epididymal WAT senescent remodeling and cardiac interstitial fibrosis, the latter being prevented by lipectomy. This finding strongly suggests visceral WAT senescence as a new target to mitigate OSA-related cardiac disorders.

Cellular origin and clonal evolution of human dedifferentiated liposarcoma

Dedifferentiated liposarcoma (DDLPS) is the most frequent high-grade soft tissue sarcoma subtype. It is characterized by a component of undifferentiated tumor cells coexisting with a component of well-differentiated adipocytic tumor cells. Both dedifferentiated (DD) and well-differentiated (WD) components exhibit MDM2 amplification, however their cellular origin remains elusive. Using single-cell RNA sequencing, DNA sequencing, in situ multiplex immunofluorescence and functional assays in paired WD and DD components from primary DDLPS tumors, we characterize the cellular heterogeneity of DDLPS tumor and micro-environment. We identify a population of tumor adipocyte stem cells (ASC) showing striking similarities with adipocyte stromal progenitors found in white adipose tissue. We show that tumor ASC harbor the ancestral genomic alterations of WD and DD components, suggesting that both derive from these progenitors following clonal evolution. Last, we show that DD tumor cells keep important biological properties of ASC including pluripotency and that their adipogenic properties are inhibited by a TGF-β-high immunosuppressive tumor micro-environment.

CRTC1 in Mc4r-expressing cells is required for peripheral metabolism and systemic energy homeostasis.

Melanocortin-4-receptor (Mc4r) is a G protein-coupled receptor (GPCR) that controls systemic energy balance by regulating food intake and energy expenditure. Although the detailed molecular mechanism remains unclear, the activation of cAMP signaling in Mc4r-expressing cells reportedly suppresses food intake and increases energy expenditure. cAMP-responsive element-binding protein-regulated transcriptional co-activator-1 (CRTC1) is selectively expressed in neuronal cells and participates in transcriptional control, thereby contributing to neuronal plasticity and energy homeostasis. Considering the cAMP-dependent regulation of CRTC1 activity, CRTC1 in Mc4r- expressing cells may contribute to energy balance regulation through the melanocortin pathway. In this context, we examined the physiological contribution of CRTC1 in Mc4r-expressing cells to energy metabolism. In this study, mice with CRTC1 deficiency in Mc4r-expressing cells exhibited 1) modest obesity, glucose intolerance, insulin resistance, hyperinsulinemia, and hyperlipidemia; 2) decreased systemic energy expenditure and thermogenesis; 3) suppression of melanocortin agonist-induced adaptation of energy expenditure and food intake; 4) impaired thermogenic programs and oxidative pathway in brown adipose tissue and skeletal muscle; and 5) enhanced lipogenic programs in the liver and white adipose tissue. These results provide novel insights into the molecular mechanisms underlying the regulation of energy balance by the melanocortin system.

Cold induces brain region-selective cell activity-dependent lipid metabolism.

It has been well documented that cold is an enhancer of lipid metabolism in peripheral tissues, yet its effect on central nervous system lipid dynamics is underexplored. It is well recognized that cold acclimations enhance adipocyte functions, including white adipose tissue (WAT) lipid lipolysis and beiging, and brown adipose tissue (BAT) thermogenesis in mammals. However, it remains unclear whether and how lipid metabolism in the brain is also under the control of cold acclimations. Here, we show that cold exposure predominantly increases the expressions of the lipid lipolysis genes and proteins within the paraventricular nucleus of the hypothalamus (PVH). Mechanistically, we find that cold activates cells within the PVH and pharmacological inactivation of cells blunts cold-induced effects on lipid peroxidation, accumulation of lipid droplets (LDs), and lipolysis in the PVH. Together, these findings suggest that PVH lipid metabolism is cold sensitive and integral to cold-induced broader regulatory responses.

Impact of Sex on the Therapeutic Efficacy of Rosiglitazone in Modulating White Adipose Tissue Function and Insulin Sensitivity.

Obesity and type 2 diabetes mellitus are global public health issues. Although males show higher obesity and insulin resistance prevalence, current treatments often neglect sex-specific differences. White adipose tissue (WAT) is crucial in preventing lipotoxicity and inflammation and has become a key therapeutic target. Rosiglitazone (RSG), a potent PPARγ agonist, promotes healthy WAT growth and mitochondrial function through MitoNEET modulation. Recent RSG-based strategies specifically target white adipocytes, avoiding side effects. Our aim was to investigate whether sex-specific differences in the insulin-sensitizing effects of RSG exist on WAT during obesity and inflammation. We used Wistar rats of both sexes fed a high-fat diet (HFD, 22.5% fat content) for 16 weeks. Two weeks before sacrifice, a group of HFD-fed rats received RSG treatment (4 mg/kg of body weight per day) within the diet. HFD male rats showed greater insulin resistance, inflammation, mitochondrial dysfunction, and dyslipidemia than females. RSG had more pronounced effects in males, significantly improving insulin sensitivity, fat storage, mitochondrial function, and lipid handling in WAT while reducing ectopic fat deposition and enhancing adiponectin signaling in the liver. Our study suggests a significant sexual dimorphism in the anti-diabetic effects of RSG on WAT, correlating with the severity of metabolic dysfunction.

IL-1β promotes adipogenesis by directly targeting adipocyte precursors

Postprandial IL-1β surges are predominant in the white adipose tissue (WAT), but its consequences are unknown. Here, we investigate the role of IL-1β in WAT energy storage and show that adipocyte-specific deletion of IL-1 receptor 1 (IL1R1) has no metabolic consequences, whereas ubiquitous lack of IL1R1 reduces body weight, WAT mass, and adipocyte formation in mice. Among all major WAT-resident cell types, progenitors express the highest IL1R1 levels. In vitro, IL-1β potently promotes adipogenesis in murine and human adipose-derived stem cells. This effect is exclusive to early-differentiation-stage cells, in which the adipogenic transcription factors C/EBPδ and C/EBPβ are rapidly upregulated by IL-1β and enriched near important adipogenic genes. The pro-adipogenic, but not pro-inflammatory effect of IL-1β is potentiated by acute treatment and blocked by chronic exposure. Thus, we propose that transient postprandial IL-1β surges regulate WAT remodeling by promoting adipogenesis, whereas chronically elevated IL-1β levels in obesity blunts this physiological function.

High-Intensity Interval Training and Vitamin D3 Supplementation Decrease CCL-5 and CCR5 Expression In White Adipose Tissue of Diabetic Rats Fed with A High-Fat Diet and Streptozotocin.

The purpose of this study was to investigate the effects of 8 weeks of high-intensity interval training (HIIT) and vitamin D3 supplementation on Chemokine (C-C motif) Ligand 5 (CCL-5) and C-C motif chemokine receptor 5 (CCR5) in the white adipose tissue (WAT) of male rats with type 2 diabetes (T2DM). The experimental study involved 40 male Wistar rats divided into 5 groups (n=8). These groups were healthy control (HC), diabetic control (DC), diabetic+HIIT (DHIIT), diabetic+vitamin D3 (DD3), and diabetic+HIIT+vitamin D3 (DHIITD3). The rats completed 8 weeks of HIIT, consisting of 12 sessions lasting 1 minute each at an intensity of 90-95% of their maximum running speed. Additionally, the rats were administered a weekly dose of 10,000 IU/kg of vitamin D3 for 8 weeks. The levels of CCL-5 (P<0.001) and CCR5 (P=0.003) were found to be higher in the DC group as compared to the HC group. However, when HIIT training and vitamin D3 were administered together, there was a decrease in CCL-5 (P=0.001) and CCR5 (P<0.001) in the DHIITD3 group (P=0.001). Similarly, vitamin D3 alone reduced CCR5 levels in the DD3 group (P< 0.001). Also, the decrease of CCR5 in the DD3 group was higher than in the DHIIT group (P=0.022), and the DHIITD3 group was higher than in the DHIIT group (P<0.001), but there was no difference between the DD3 and DHIITD3 groups (P≥0.05). The results indicate that combining HIIT training with vitamin D3 has a greater effect on reducing the expression of CCL-5 and CCR5 in the white adipose tissue of rats with type 2 diabetes induced by streptozotocin (STZ) and a high-fat diet (HFD), compared to the effects of each one alone. It is recommended that the study be conducted by measuring the variables involved in the mechanisms and the changes in CCL-5 and CCR5.

Hypoxia and Foxn1 alter the proteomic signature of dermal fibroblasts to redirect scarless wound healing to scar-forming skin wound healing in Foxn1−/− mice

BackgroundFoxn1−/− deficient mice are a rare model of regenerative skin wound healing among mammals. In wounded skin, the transcription factor Foxn1 interacting with hypoxia-regulated factors affects re-epithelialization, epithelial-mesenchymal transition (EMT) and dermal white adipose tissue (dWAT) reestablishment and is thus a factor regulating scar-forming/reparative healing. Here, we hypothesized that transcriptional crosstalk between Foxn1 and Hif-1α controls the switch from scarless (regenerative) to scar-present (reparative) skin wound healing. To verify this hypothesis, we examined (i) the effect of hypoxia/normoxia and Foxn1 signalling on the proteomic signature of Foxn1−/− (regenerative) dermal fibroblasts (DFs) and then (ii) explored the effect of Hif-1α or Foxn1/Hif-1α introduced by a lentiviral (LV) delivery vector to injured skin of regenerative Foxn1−/− mice with particular attention to the remodelling phase of healing.ResultsWe showed that hypoxic conditions and Foxn1 stimulation modified the proteome of Foxn1−/− DFs. Hypoxic conditions upregulated DF protein profiles, particularly those related to extracellular matrix (ECM) composition: plasminogen activator inhibitor-1 (Pai-1), Sdc4, Plod2, Plod1, Lox, Loxl2, Itga2, Vldlr, Ftl1, Vegfa, Hmox1, Fth1, and F3. We found that Pai-1 was stimulated by hypoxic conditions in regenerative Foxn1−/− DFs but was released by DFs to the culture media exclusively upon hypoxia and Foxn1 stimulation. We also found higher levels of Pai-1 protein in DFs isolated from Foxn1+/+ mice (reparative/scar-forming) than in DFs isolated from Foxn1−/− (regenerative/scarless) mice and triggered by injury increase in Foxn1 and Pai-1 protein in the skin of mice with active Foxn1 (Foxn1+/+ mice). Then, we demonstrated that the introduction of Foxn1 and Hif-1α via lentiviral injection into the wounded skin of regenerative Foxn1−/− mice activates reparative/scar-forming healing by increasing the wounded skin area and decreasing hyaluronic acid deposition and the collagen type III to I ratio. We also identified a stimulatory effect of LV-Foxn1 + LV-Hif-1α injection in the wounded skin of Foxn1−/− mice on Pai-1 protein levels.ConclusionsThe present data highlight the effect of hypoxia and Foxn1 on the protein profile and functionality of regenerative Foxn1−/− DFs and demonstrate that the introduction of Foxn1 and Hif-1α into the wounded skin of regenerative Foxn1−/− mice activates reparative/scar-forming healing.

Hypothalamic SLC7A14 accounts for aging-reduced lipolysis in white adipose tissue of male mice

The central nervous system has been implicated in the age-induced reduction in adipose tissue lipolysis. However, the underlying mechanisms remain unclear. Here, we show the expression of SLC7A14 is reduced in proopiomelanocortin (POMC) neurons of aged mice. Overexpression of SLC7A14 in POMC neurons alleviates the aging-reduced lipolysis, whereas SLC7A14 deletion mimics the age-induced lipolysis impairment. Metabolomics analysis reveals that POMC SLC7A14 increased taurochenodeoxycholic acid (TCDCA) content, which mediates the SLC7A14 knockout- or age-induced WAT lipolysis impairment. Furthermore, SLC7A14-increased TCDCA content is dependent on intestinal apical sodium-dependent bile acid transporter (ASBT), which is regulated by intestinal sympathetic afferent nerves. Finally, SLC7A14 regulates the intestinal sympathetic afferent nerves by inhibiting mTORC1 signaling through inhibiting TSC1 phosphorylation. Collectively, our study suggests the function for central SLC7A14 and an upstream mechanism for the mTORC1 signaling pathway. Moreover, our data provides insights into the brain–gut–adipose tissue crosstalk in age-induced lipolysis impairment.