Regulation Of Adipose Tissue Function Research Articles

Natural H2S-donors: A new pharmacological opportunity for the management of overweight and obesity.

The prevalence of overweight and obesity has progressively increased in the last few years, becoming a real threat to healthcare systems. To date, the clinical management of body weight gain is an unmet medical need, as there are few approved anti-obesity drugs and most require an extensive monitoring and vigilance due to risk of adverse effects and poor patient adherence/persistence. Growing evidence has shown that the gasotransmitter hydrogen sulfide (H2S) and, therefore, H2S-donors could have a central role in the prevention and treatment of overweight/obesity. The main natural sources of H2S-donors are plants from the Alliaceae (garlic and onion), Brassicaceae (e.g., broccoli, cabbage, and wasabi), and Moringaceae botanical families. In particular, polysulfides and isothiocyanates, which slowly release H2S, derive from the hydrolysis of alliin from Alliaceae and glucosinolates from Brassicaceae/Moringaceae, respectively. In this review, we describe the emerging role of endogenous H2S in regulating adipose tissue function and the potential efficacy of natural H2S-donors in animal models of overweight/obesity, with a final focus on the preliminary results from clinical trials. We conclude that organosulfur-containing plants and their extracts could be used before or in combination with conventional anti-obesity agents to improve treatment efficacy and reduce inflammation in obesogenic conditions. However, further high-quality studies are needed to firmly establish their clinical efficacy.

MiR-221-3p/222-3p Cluster Expression in Human Adipose Tissue Is Related to Obesity and Type 2 Diabetes.

The progression of obesity and type 2 diabetes (T2D) is intricately linked with adipose tissue (AT) angiogenesis. Despite an established network of microRNAs (miRNAs) regulating AT function, the specific role of angiogenic miRNAs remains less understood. The miR-221/222 cluster has recently emerged as being associated with antiangiogenic activity. However, no studies have explored its role in human AT amidst the concurrent development of obesity and T2D. Therefore, this study aims to investigate the association between the miR-221-3p/222-3p cluster in human AT and its regulatory network with obesity and T2D. MiR-221-3p/222-3p and their target gene (TG) expression levels were quantified through qPCR in visceral (VAT) and subcutaneous (SAT) AT from patients (n = 33) categorized based on BMI as normoweight (NW) and obese (OB) and by glycemic status as normoglycemic (NG) and type 2 diabetic (T2D) subjects. In silico analyses of miR-221-3p/222-3p and their TGs were conducted to identify pertinent signaling pathways. The results of a multivariate analysis, considering the simultaneous expression of miR-221-3p and miR-222-3p as dependent variables, revealed statistically significant distinctions when accounting for variables such as tissue depot, obesity, sex, and T2D as independent factors. Furthermore, both miRNAs and their TGs exhibited differential expression patterns based on obesity severity, glycemic status, sex, and type of AT depot. Our in silico analysis indicated that miR-221-3p/222-3p cluster TGs predominantly participate in angiogenesis, WNT signaling, and apoptosis pathways. In conclusion, these findings underscore a promising avenue for future research, emphasizing the miR-221-3p/222-3p cluster and its associated regulatory networks as potential targets for addressing obesity and related metabolic disorders.

Whole-Mount Imaging of Adipose Tissue Macrophages.

The adipose tissue comprises highly heterogeneous macrophage populations, which play critical roles in the regulation of adipose tissue function and dysfunction during health and disease. Whole-amount staining is a powerful technique for macrophage characterization within the 3D environment of the adipose tissue, enabling the visualization of different macrophage populations and their interaction with other cells within their in vivo niche. Due to the high-fat content and softness, freezing and sectioning of adipose tissue is difficult, and distortion of tissue morphology typically occurs, especially in the case of white adipose tissue. We describe here a whole-mount staining alternative for adipose tissue imaging that preserves all structures and allows high-resolution image acquisition. We address in a step-by-step manner how to perform immunofluorescence staining of different fat pads and how to optimally visualize cellular and acellular (extracellular matrix) constituents of the adipose tissue and its vasculature, as well as resident and infiltrating macrophage populations.

The Transcription Factor HOXA5: Novel Insights into Metabolic Diseases and Adipose Tissue Dysfunction.

The transcription factor HOXA5, from the HOX gene family, has long been studied due to its critical role in physiological activities in normal cells, such as organ development and body patterning, and pathological activities in cancer cells. Nonetheless, recent evidence supports the hypothesis of a role for HOXA5 in metabolic diseases, particularly in obesity and type 2 diabetes (T2D). In line with the current opinion that adipocyte and adipose tissue (AT) dysfunction belong to the group of primary defects in obesity, linking this condition to an increased risk of insulin resistance (IR) and T2D, the HOXA5 gene has been shown to regulate adipocyte function and AT remodeling both in humans and mice. Epigenetics adds complexity to HOXA5 gene regulation in metabolic diseases. Indeed, epigenetic mechanisms, specifically DNA methylation, influence the dynamic HOXA5 expression profile. In human AT, the DNA methylation profile at the HOXA5 gene is associated with hypertrophic obesity and an increased risk of developing T2D. Thus, an inappropriate HOXA5 gene expression may be a mechanism causing or maintaining an impaired AT function in obesity and potentially linking obesity to its associated disorders. In this review, we integrate the current evidence about the involvement of HOXA5 in regulating AT function, as well as its association with the pathogenesis of obesity and T2D. We also summarize the current knowledge on the role of DNA methylation in controlling HOXA5 expression. Moreover, considering the susceptibility of epigenetic changes to reversal through targeted interventions, we discuss the potential therapeutic value of targeting HOXA5 DNA methylation changes in the treatment of metabolic diseases.

CD47 antisense oligonucleotide treatment attenuates obesity and its-associated metabolic dysfunction

Previous study from our lab has revealed a new role of CD47 in regulating adipose tissue function, energy homeostasis and the development of obesity and metabolic disease in CD47 deficient mice. In this study, the therapeutic potential of an antisense oligonucleotide (ASO) targeting to CD47 in obesity and its-associated complications was determined in two obese mouse models (diet induced and genetic models). In diet induced obesity, male C57BL6 mice were fed with high fat (HF) diet to induce obesity and then treated with CD47ASO or control ASO for 8 weeks. In genetic obese mouse model, male six-week old ob/ob mice were treated with ASOs for 9 weeks. We found that CD47ASO treatment reduced HF diet-induced weight gain, decreased fat mass, prevented dyslipidemia, and improved glucose tolerance. These changes were accompanied by reduced inflammation in white adipose tissue and decreased hepatic steatosis. This protection was also seen in CD47ASO treated ob/ob mice. Mechanistically, CD47ASO treatment increased mice physical activity and energy expenditure, contributing to weight loss and improved metabolic outcomes in obese mice. Collectively, these findings suggest that CD47ASO might serve as a new treatment option for obesity and its-associated metabolic complications.

Methods for Single Cell Transcriptomic Analysis of Adipose Tissue.

The development of single cell approaches has facilitated the investigation of cellular heterogeneity and cell type-specific gene expression in complex tissues. Adipose tissue depots contain lipid storing adipocytes as well as a diverse array of cell types that form the adipocyte niche and regulate adipose tissue function. Here, I describe two protocols for the isolation of single cells and nuclei from white and brown adipose tissue. Additionally, I provide a detailed workflow for isolation of cell type- or lineage-specific single nuclei using nuclear tagging and translating ribosome affinity purification (NuTRAP) mouse models.

Effects of the Myokine Irisin on Stromal Cells from Swine Adipose Tissue.

Irisin is a hormone able to reproduce some of the positive effects of physical activity and diet. Recently, we demonstrated the presence of Irisin at the ovarian level as a potential physiological regulator of follicular function. Adipose tissue is crucial for reproductive function through its metabolic activity and the production of adipokines. At present, the exact nature of adipocyte precursors is still under debate, but an important role has been assigned to the population of adipose tissue mesenchymal stromal cells (ASCs) of perivascular origin. It should be noted that, when appropriately stimulated, ASCs can differentiate into preadipocytes and, subsequently, adipocytes. Therefore, this present study was undertaken to explore the potential effect of Irisin on ASCs, known for their high differentiative potential. Since Irisin expression in ASCs was confirmed by PCR, we tested its potential effects on the main functional activities of these cells, including proliferation (BrdU uptake); metabolic activity (ATP production); redox status, evaluated as the generation of free molecules such as superoxide anion and nitric oxide; and scavenger activities, assessed as both enzymatic (superoxide dismutase) and non-enzymatic antioxidant power. Moreover, we tested the effect of Irisin on ASCs adipogenic differentiation. BrdU uptake was significantly (p < 0.001) inhibited by Irisin, while ATP production was significantly (p < 0.05) increased. Both superoxide anion and nitric oxide generation were significantly increased (p < 0.001) by Irisin, while scavenger activity was significantly reduced (p < 0.05). Irisin was found to significantly (p < 0.05) inhibit ASCs adipogenic differentiation. Taken together, the present results suggest a potential local role of Irisin in the regulation of adipose tissue function.

Gasdermin D Deficiency Does Not Protect Mice from High-Fat Diet-Induced Glucose Intolerance and Adipose Tissue Inflammation.

The adipose tissue NLRP3 inflammasome has recently emerged as a contributor to obesity-related metabolic inflammation. Recent studies have demonstrated that the activation of the NLRP3 inflammasome cleaves gasdermin D (GSDMD) and induces pyroptosis, a proinflammatory programmed cell death. However, whether GSDMD is involved in the regulation of adipose tissue function and the development of obesity-induced metabolic disease remains unknown. The aim of the present study was to investigate the role of GSDMD in adipose tissue inflammation as well as whole-body metabolism using GSDMD-deficient mice fed a high-fat diet (HFD) for 30 weeks. The effects of GSDMD deficiency on adipose tissue, liver, and isolated macrophages from wild-type (WT) and GSDMD knockout (KO) mice were examined. In addition, 3T3-L1 cells were used to examine the expression of GSDMD during adipogenesis. The results demonstrate that although HFD-induced inflammation was partly ameliorated in isolated macrophages and liver, adipose tissue remained unaffected by GSDMD deficiency. Compared with the WT HFD mice, GSDMD KO HFD mice exhibited a mild increase in HFD-induced glucose intolerance with increased systemic and adipose tissue IL-1β levels. Interestingly, GSDMD deficiency caused accumulation of fat mass when challenged with HFD, partly by suppressing the expression of peroxisome proliferator-activated receptor gamma (PPARγ). The expression of GSDMD mRNA and protein was dramatically suppressed during adipocyte differentiation and was inversely correlated with PPARγ expression. Together, these findings indicate that GSDMD is not a prerequisite for HFD-induced adipose tissue inflammation and suggest a noncanonical function of GSDMD in regulation of fat mass through PPARγ.

A MDM2 inhibitor MX69 inhibits adipocytes adipogenesis and differentiation

Adipose tissue, a key regulator of systemic energy homeostasis, can synthesize and store triglycerides to meet long-term energy demands. In response to nutrient overload, adipose tissue expands by hypertrophy or hyperplasia. As an oncogene, MDM2 has exerted diverse biological activities including human development, tissue regeneration, and inflammation, in addition to major oncogenic activities. Recently, some studies indicated that MDM2 plays an important role in adipose tissue function. However, the role of MX69, a MDM2 inhibitor, in adipose tissue function has not been fully elucidated. Here, we administered MX69 intraperitoneally to high-fat diet-induced obesity (DIO) wild type C57BL/6 mice and found that MX69 could promote the body weight and white adipose tissue weight of DIO mice. Moreover, MX69 had no effects on glucose tolerance and insulin sensitivity in DIO mice. And MX69 treatment decreased the size of adipocytes and fat deposition in adipose tissue and inhibited 3T3-L1 preadipocytes differentiation. Mechanistically, MX69 inhibited the protein levels of MDM2 and the mRNA levels of genes related to adipogenesis and differentiation. In summary, our results indicated that MDM2 has a crucial and complex role in regulating adipose tissue function.

Corin Deficiency Alters Adipose Tissue Phenotype and Impairs Thermogenesis in Mice.

Simple SummaryThermoregulation is of fundamental significance for all endothermic animals. Corin is a protease that activates atrial natriuretic peptide (ANP), a cardiac hormone critical in cardiovascular homeostasis and adipose tissue function. In this study, we report that in mice, corin deficiency increased the weight and cell size in white adipose tissue, decreased thermogenic gene profiles in brown adipose tissue, and impaired thermogenic responses upon cold exposure, leading to hypothermia. In brown adipose tissue from corin-deficient mice, the ANP-mediated p38 mitogen-activated protein kinase and uncoupling protein 1 signaling mechanism is compromised. These findings indicate a crucial role of corin in modulating adipose tissue function and thermogenesis upon cold exposure in mice.Atrial natriuretic peptide (ANP) is a key regulator in body fluid balance and cardiovascular biology. In addition to its role in enhancing natriuresis and vasodilation, ANP increases lipolysis and thermogenesis in adipose tissue. Corin is a protease responsible for ANP activation. It remains unknown if corin has a role in regulating adipose tissue function. Here, we examined adipose tissue morphology and function in corin knockout (KO) mice. We observed increased weights and cell sizes in white adipose tissue (WAT), decreased levels of uncoupling protein 1 (Ucp1), a brown adipocyte marker in WAT and brown adipose tissue (BAT), and suppressed thermogenic gene expression in BAT from corin KO mice. At regular room temperature, corin KO and wild-type mice had similar metabolic rates. Upon cold exposure at 4 °C, corin KO mice exhibited impaired thermogenic responses and developed hypothermia. In BAT from corin KO mice, the signaling pathway of p38 mitogen-activated protein kinase, peroxisome proliferator-activated receptor c coactivator 1a, and Ucp1 was impaired. In cell culture, ANP treatment increased Ucp1 expression in BAT-derived adipocytes from corin KO mice. These data indicate that corin mediated-ANP activation is an important hormonal mechanism in regulating adipose tissue function and body temperature upon cold exposure in mice.

FC028: Characterization of Adipocyte Size and Glucose Uptake in Adipose Tissue with Focus on Different Perirenal Fat Depots

Abstract BACKGROUND AND AIMS Previous studies have suggested that the anatomical location of adipose tissue, and the characteristics of the adipocytes regulating adipose tissue function may be of importance for normal renal function and disease. However, in humans, the adipocyte size and metabolism of the fat depots surrounding the kidney have not been thoroughly characterized. The aim of this study was therefore to characterize adipocyte size and glucose uptake in human perirenal, renal sinus and paranephric adipose tissue. SUBJECTS AND METHODS A total of 25 healthy kidney donors [13 (50%) men, age 48 ± 11 years and BMI 25.7 ± 3.1 kg/m2] were included. Perirenal, renal sinus, paranephric, omental and subcutaneous adipose tissue were collected during laparoscopic unilateral nephrectomy. Adipocyte diameter, basal glucose uptake (no insulin) and insulin-stimulated glucose uptake (25 and 1000 µU/mL) were measured in isolated adipocytes from the different tissues. RESULTS The mean adipocyte cell diameters in the renal fat depots (perirenal, renal sinus and paranephric) were smaller than those in omental and subcutaneous tissue (mean ± sd; 69.3 ± 15.5, 65.5 ± 13.5 and 75.9 ± 16.5 versus 80.3 ± 20.5 and 85.5 ± 16.7 µm, respectively) with adipocytes from the renal sinus fat depot having the smallest cell diameter. Detailed data are displayed in Fig. 1. There were no significant gender differences in cell size and adipocyte size from the different depots did not correlate with body mass index (BMI). Insulin resistance index (HOMA-IR) correlated positively and significantly to adipocyte size in the omental (r = 0.607; P = 0.008), perirenal (r = 0.443; P = 0.027) and paranephric (r = 0.479; P = 0.015) depots. Insulin (both with 25 and 1000 µU/mL) significantly up-regulated glucose uptake in subcutaneous (1.6 and 1.9-fold; P < 0.05), perirenal (1.7 and 2.0-fold; P < 0.01) and paranephric (1.5 and 1.6-folds; P < 0.01) adipocytes, compared with basal (no insulin) as shown in Fig. 2. Interestingly, glucose uptake per cell surface was higher in renal sinus than omental adipocytes (basal (no insulin) 1.2-fold; P < 0.001, physiological (25 µU/mL) and supraphysiological (1000 µU/mL) both 1.3-fold higher; P < 0.001) than omental adipocytes (comparison not shown). CONCLUSION This study in healthy kidney donors indicate differences in different fat depots surrounding the kidney that may be of importance for renal function and disease. The fat depot in the renal sinus, with the smallest adipocytes and potentially a higher glucose uptake, is of specific interest. Detailed metabolic characterization of these fat depots is ongoing. Comparison of adipocyte diameter between the different adipose tissue depots: subcutaneous (n = 24), omental (n = 18), perirenal (n = 25), renal sinus (n = 21) and paranephric adipose tissue (n = 25); Values are mean with SEM as data were normally distributed. **P < 0.01 and ***P < 0.001. Physiological and supraphysiological effect of insulin (25 and 1000 µU/mL) on glucose uptake compared with basal (no insulin) by cell surface in adipocytes isolated from subcutaneous (n = 6), omental (n = 3), perirenal (n = 21), renal sinus (n = 4) and paranephric (n = 18) adipose tissue depots, respectively. Values are median and interquartile range as data were not normally distributed. *P < 0.05, **P < 0.01.

Differing impact of phosphoglycerate mutase 1-deficiency on brown and white adipose tissue

SummaryBrown adipose tissue (BAT) is a metabolically active organ that contributes to the thermogenic response to cold exposure. In addition, other thermogenic cells termed beige adipocytes are generated in white adipose tissue (WAT) by cold exposure. Although activation of brown/beige adipose tissue is associated with mobilization of both glucose and lipids, few studies have focused on the role of glycolytic enzymes in regulating adipose tissue function. We generated mouse models with specific deletion of the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) from adipose tissue. Deletion of Pgam1 from both BAT and WAT promoted whitening of BAT with beiging of visceral WAT, whereas deletion of Pgam1 from BAT alone led to whitening of BAT without beiging of WAT. Our results demonstrate a potential role of glycolytic enzymes in beiging of visceral WAT and suggest that PGAM1 would be a novel therapeutic target in obesity and diabetes.

Immune Cell Regulation of White Adipose Progenitor Cell Fate.

Adipose tissue is essential for energy storage and endocrine regulation of metabolism. Imbalance in energy intake and expenditure result in obesity causing adipose tissue dysfunction. This alters cellular composition of the stromal cell populations and their function. Moreover, the individual cellular composition of each adipose tissue depot, regulated by environmental factors and genetics, determines the ability of the depots to expand and maintain its endocrine and storage function. Thus, stromal cells modulate adipocyte function and vice versa. In this mini-review we discuss heterogeneity in terms of composition and fate of adipose progenitor subtypes and their interactions with and regulation by different immune cell populations. Immune cells are the most diverse cell populations in adipose tissue and play essential roles in regulating adipose tissue function via interaction with adipocytes but also with adipocyte progenitors. We specifically discuss the role of macrophages, mast cells, innate lymphoid cells and T cells in the regulation of adipocyte progenitor proliferation, differentiation and lineage commitment. Understanding the factors and cellular interactions regulating preadipocyte expansion and fate decision will allow the identification of novel mechanisms and therapeutic strategies to promote healthy adipose tissue expansion without systemic metabolic impairment.

Organization of sympathetic innervation of interscapular brown adipose tissue in the mouse.

The interscapular brown adipose tissue (iBAT) is under sympathetic control, and recent studies emphasized the importance of efferent sympathetic and afferent sensory or humoral feedback systems to regulate adipose tissue function and overall metabolic health. However, functional studies of the sympathetic nervous system in the mouse are limited, because details of anatomy and fine structure are lacking. Here, we used reporter mice for tyrosine hydroxylase expressing neurons (TH:tomato mice), iDISCO tissue clearance, confocal, lightsheet, and electron microscopy to clarify that (a) iBAT receives sympathetic input via dorsal rami (instead of often cited intercostal nerves); (b) dorsal rami T1-T5 correspond to the postganglionic input from sympathetic chain ganglia (stellate/T1-T5); (c) dorsal rami serve as conduits for sympathetic axons that branch off in finer nerve bundles to enter iBAT; (d) axonal varicosities show strong differential innervation of brown (dense innervation) versus white (sparse innervation) adipocytes, that surround the core iBAT in the mouse and are intermingled in human adipose tissues, (e) axonal varicosities can form neuro-adipocyte junctions with brown adipocytes. Taken together, we demonstrate that sympathetic iBAT innervation is organized by specific nerves and terminal structures that can be surgically and genetically accessed for neuromodulatory purposes.

Assessing the Contribution of Relative Macrophage Frequencies to Subcutaneous Adipose Tissue.

Background: Macrophages play an important role in regulating adipose tissue function, while their frequencies in adipose tissue vary between individuals. Adipose tissue infiltration by high frequencies of macrophages has been linked to changes in adipokine levels and low-grade inflammation, frequently associated with the progression of obesity. The objective of this project was to assess the contribution of relative macrophage frequencies to the overall subcutaneous adipose tissue gene expression using publicly available datasets.Methods: Seven publicly available microarray gene expression datasets from human subcutaneous adipose tissue biopsies (n = 519) were used together with TissueDecoder to determine the adipose tissue cell-type composition of each sample. We divided the subjects in four groups based on their relative macrophage frequencies. Differential gene expression analysis between the high and low relative macrophage frequencies groups was performed, adjusting for sex and study. Finally, biological processes were identified using pathway enrichment and network analysis.Results: We observed lower frequencies of adipocytes and higher frequencies of adipose stem cells in individuals characterized by high macrophage frequencies. We additionally studied whether, within subcutaneous adipose tissue, interindividual differences in the relative frequencies of macrophages were reflected in transcriptional differences in metabolic and inflammatory pathways. Adipose tissue of individuals with high macrophage frequencies had a higher expression of genes involved in complement activation, chemotaxis, focal adhesion, and oxidative stress. Similarly, we observed a lower expression of genes involved in lipid metabolism, fatty acid synthesis, and oxidation and mitochondrial respiration.Conclusion: We present an approach that combines publicly available subcutaneous adipose tissue gene expression datasets with a deconvolution algorithm to calculate subcutaneous adipose tissue cell-type composition. The results showed the expected increased inflammation gene expression profile accompanied by decreased gene expression in pathways related to lipid metabolism and mitochondrial respiration in subcutaneous adipose tissue in individuals characterized by high macrophage frequencies. This approach demonstrates the hidden strength of reusing publicly available data to gain cell-type-specific insights into adipose tissue function.

The Role of Peptide Hormones Discovered in the 21st Century in the Regulation of Adipose Tissue Functions.

Peptide hormones play a prominent role in controlling energy homeostasis and metabolism. They have been implicated in controlling appetite, the function of the gastrointestinal and cardiovascular systems, energy expenditure, and reproduction. Furthermore, there is growing evidence indicating that peptide hormones and their receptors contribute to energy homeostasis regulation by interacting with white and brown adipose tissue. In this article, we review and discuss the literature addressing the role of selected peptide hormones discovered in the 21st century (adropin, apelin, elabela, irisin, kisspeptin, MOTS-c, phoenixin, spexin, and neuropeptides B and W) in controlling white and brown adipogenesis. Furthermore, we elaborate how these hormones control adipose tissue functions in vitro and in vivo.

The Interplay between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship between Adiposopathy and Cardiometabolic Diseases?

Angiopoietin-like proteins, namely ANGPTL3-4-8, are known as regulators of lipid metabolism. However, recent evidence points towards their involvement in the regulation of adipose tissue function. Alteration of adipose tissue functions (also called adiposopathy) is considered the main inducer of metabolic syndrome (MS) and its related complications. In this review, we intended to analyze available evidence derived from experimental and human investigations highlighting the contribution of ANGPTLs in the regulation of adipocyte metabolism, as well as their potential role in common cardiometabolic alterations associated with adiposopathy. We finally propose a model of ANGPTLs-based adipose tissue dysfunction, possibly linking abnormalities in the angiopoietins to the induction of adiposopathy and its related disorders.

Transcriptomic profiling of adipose tissue inflammation, remodeling, and lipid metabolism in periparturient dairy cows (Bos taurus)

BackgroundPeriparturient cows release fatty acid reserves from adipose tissue (AT) through lipolysis in response to the negative energy balance induced by physiological changes related to parturition and the onset of lactation. However, lipolysis causes inflammation and structural remodeling in AT that in excess predisposes cows to disease. The objective of this study was to determine the effects of the periparturient period on the transcriptomic profile of AT using NGS RNAseq.ResultsSubcutaneous AT samples were collected from Holstein cows (n = 12) at 11 ± 3.6 d before calving date (PreP) and at 6 ± 1d (PP1) and 13 ± 1.4d (PP2) after parturition. Differential expression analyses showed 1946 and 1524 DEG at PP1 and PP2, respectively, compared to PreP. Functional Enrichment Analysis revealed functions grouped in categories such as lipid metabolism, molecular transport, energy production, inflammation, and free radical scavenging to be affected by parturition and the onset of lactation (FDR < 0.05). Inflammation related genes such as TLR4 and IL6 were categorized as upstream lipolysis triggers. In contrast, FASN, ELOVL6, ACLS1, and THRSP were identified as upstream inhibitors of lipid synthesis. Complement (C3), CXCL2, and HMOX1 were defined as links between inflammatory pathways and those involved in the generation of reactive oxygen species.ConclusionsResults offer a comprehensive characterization of gene expression dynamics in periparturient AT, identify upstream regulators of AT function, and demonstrate complex interactions between lipid mobilization, inflammation, extracellular matrix remodeling, and redox signaling in the adipose organ.

Adipose Tissue Immunomodulation: A Novel Therapeutic Approach in Cardiovascular and Metabolic Diseases.

Adipose tissue is a critical regulator of systemic metabolism and bodily homeostasis as it secretes a myriad of adipokines, including inflammatory and anti-inflammatory cytokines. As the main storage pool of lipids, subcutaneous and visceral adipose tissues undergo marked hypertrophy and hyperplasia in response to nutritional excess leading to hypoxia, adipokine dysregulation, and subsequent low-grade inflammation that is characterized by increased infiltration and activation of innate and adaptive immune cells. The specific localization, physiology, susceptibility to inflammation and the heterogeneity of the inflammatory cell population of each adipose depot are unique and thus dictate the possible complications of adipose tissue chronic inflammation. Several lines of evidence link visceral and particularly perivascular, pericardial, and perirenal adipose tissue inflammation to the development of metabolic syndrome, insulin resistance, type 2 diabetes and cardiovascular diseases. In addition to the implication of the immune system in the regulation of adipose tissue function, adipose tissue immune components are pivotal in detrimental or otherwise favorable adipose tissue remodeling and thermogenesis. Adipose tissue resident and infiltrating immune cells undergo metabolic and morphological adaptation based on the systemic energy status and thus a better comprehension of the metabolic regulation of immune cells in adipose tissues is pivotal to address complications of chronic adipose tissue inflammation. In this review, we discuss the role of adipose innate and adaptive immune cells across various physiological and pathophysiological states that pertain to the development or progression of cardiovascular diseases associated with metabolic disorders. Understanding such mechanisms allows for the exploitation of the adipose tissue-immune system crosstalk, exploring how the adipose immune system might be targeted as a strategy to treat cardiovascular derangements associated with metabolic dysfunctions.

Pyrazolone derivative C29 protects against HFD-induced obesity in mice via activation of AMPK in adipose tissue.

Beige adipocytes have been considered as a potential strategy in anti-obesity therapy because of its thermogenic capacity. AMP-activated protein kinase (AMPK) plays important roles in regulating adipose tissue function. C29 is a novel pyrazolone derivative with AMPK activity. In the current study, we investigated the role of C29 in the regulation of thermogenesis using differentiated adipocytes and diet-induced obese mice, and explored the mechanisms that might be involved in energy expenditure via adipocyte AMPK activation. We showed that treatment with C29 (2.5-10 μM) concentration-dependently increased thermogenesis in differentiated preadipocytes separated from inguinal white adipose tissue (iWAT), evidenced by increased expression levels of thermogenesis markers such as Ucp1, Pgc-1α, Dio2, Prdm16, Cox7a1, Cox8b, Elovl3, and Cidea, fatty acid oxidation (FAO) genes including Cpt1a, Lcad and Pparα, as well as beige-selective genes such as Cd137, Tmem26, Slc27a1, and Tbx1. In high-fat diet (HFD)-fed mice, oral administration of C29 (30 mg·kg-1·day-1) for 9 weeks alleviated HFD-induced obesity, promoted energy expenditure and modulated iWAT browning. However, these effects were not observed in adipose-specific AMPKα1/α2 knockout (AKO) mice following C29 administration. Together, this study demonstrates that C29 regulates energy balance via adipocyte AMPK. Our findings show that the discovery of AMPK activators that specifically target adipose tissue may have therapeutic potential for treating obesity-related metabolic diseases.