Adipocyte-Specific ACKR3 Regulates Lipid Levels in Adipose Tissue.
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ABSTRACT:
SUBMITTER: Gencer S
PROVIDER: S-EPMC8067615 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveBeclin1 is a core molecule of the macroautophagy machinery. Although dysregulation of macroautophagy is known to be involved in metabolic disorders, the function of Beclin1 in adipocyte metabolism has not been investigated. In the present study, we aimed to study the role of Beclin1 in lipolysis and mitochondrial homeostasis of adipocytes.MethodsAutophagic flux during lipolysis was examined in adipocytes cultured in vitro and in the adipose tissue of mice. Adipocyte-specific Beclin1 knockout (KO) mice were used to investigate the activities of Beclin1 in adipose tissues.ResultscAMP/PKA signaling increased the autophagic flux in adipocytes differentiated from C3H10T1/2 cells. In vivo autophagic flux was higher in the brown adipose tissue (BAT) than that in the white adipose tissue and was further increased by the ?3 adrenergic receptor agonist CL316243. In addition, surgical denervation of BAT greatly reduced autophagic flux, indicating that sympathetic nerve activity is a major regulator of tissue autophagy. Adipocyte-specific KO of Beclin1 led to a hypertrophic enlargement of lipid droplets in BAT and impaired CL316243-induced lipolysis/lipid mobilization and energy expenditure. While short-term effects of Beclin1 deletion were characterized by an increase in mitochondrial proteins, long-term Beclin1 deletion led to severe disruption of autophagy, resulting in mitochondrial loss, and dramatically reduced the expression of genes involved in lipid metabolism. Consequently, adipose tissue underwent increased activation of cell death signaling pathways, macrophage recruitment, and inflammation, particularly in BAT.ConclusionsThe present study demonstrates the critical roles of Beclin1 in the maintenance of lipid metabolism and mitochondrial homeostasis in adipose tissues.
| S-EPMC7235646 | biostudies-literature
Project description:ObjectiveInsulin suppresses adipose tissue lipolysis after a meal, playing a key role in metabolic homeostasis. This is mediated via the kinase Akt and its substrate phosphodiesterase 3B (PDE3B). Once phosphorylated and activated, PDE3B hydrolyses cAMP leading to the inactivation of cAMP-dependent protein kinase (PKA) and suppression of lipolysis. However, several gaps have emerged in this model. Here we investigated the role of the PDE3B-interacting protein, α/β-hydrolase ABHD15 in this process.MethodsLipolysis, glucose uptake, and signaling were assessed in ABHD15 knock down and knock out adipocytes and fat explants in response to insulin and/or β-adrenergic receptor agonist. Glucose and fatty acid metabolism were determined in wild type and ABHD15-/- littermate mice.ResultsDeletion of ABHD15 in adipocytes resulted in a significant defect in insulin-mediated suppression of lipolysis with no effect on insulin-mediated glucose uptake. ABHD15 played a role in suppressing PKA signaling as phosphorylation of the PKA substrate Perilipin-1 remained elevated in response to insulin upon ABHD15 deletion. ABHD15-/- mice had normal glucose metabolism but defective fatty acid metabolism: plasma fatty acids were elevated upon fasting and in response to insulin, and this was accompanied by elevated liver triglycerides upon β-adrenergic receptor activation. This is likely due to hyperactive lipolysis as evident by the larger triglyceride depletion in brown adipose tissue in these mice. Finally, ABHD15 protein levels were reduced in adipocytes from mice fed a Western diet, further implicating this protein in metabolic homeostasis.ConclusionsCollectively, ABHD15 regulates adipocyte lipolysis and liver lipid accumulation, providing novel therapeutic opportunities for modulating lipid homeostasis in disease.
| S-EPMC6601125 | biostudies-literature
Project description:ObjectiveCanonical Wnt/β-catenin signaling is a well-studied endogenous regulator of mesenchymal cell fate determination, promoting osteoblastogenesis and inhibiting adipogenesis. However, emerging genetic evidence in humans links a number of Wnt pathway members to body fat distribution, obesity, and metabolic dysfunction, suggesting that this pathway also functions in adipocytes. Recent studies in mice have uncovered compelling evidence that the Wnt signaling pathway plays important roles in adipocyte metabolism, particularly under obesogenic conditions. However, complexities in Wnt signaling and differences in experimental models and approaches have thus far limited our understanding of its specific roles in this context.MethodsTo investigate roles of the canonical Wnt pathway in the regulation of adipocyte metabolism, we generated adipocyte-specific β-catenin (β-cat) knockout mouse and cultured cell models. We used RNA sequencing, ChIP sequencing, and molecular approaches to assess expression of Wnt targets and lipogenic genes. We then used functional assays to evaluate effects of β-catenin deficiency on adipocyte metabolism, including lipid and carbohydrate handling. In mice maintained on normal chow and high-fat diets, we assessed the cellular and functional consequences of adipocyte-specific β-catenin deletion on adipose tissues and systemic metabolism.ResultsWe report that in adipocytes, the canonical Wnt/β-catenin pathway regulates de novo lipogenesis (DNL) and fatty acid monounsaturation. Further, β-catenin mediates effects of Wnt signaling on lipid metabolism in part by transcriptional regulation of Mlxipl and Srebf1. Intriguingly, adipocyte-specific loss of β-catenin is sensed and defended by CD45-/CD31- stromal cells to maintain tissue-wide Wnt signaling homeostasis in chow-fed mice. With long-term high-fat diet, this compensatory mechanism is overridden, revealing that β-catenin deletion promotes resistance to diet-induced obesity and adipocyte hypertrophy and subsequent protection from metabolic dysfunction.ConclusionsTaken together, our studies demonstrate that Wnt signaling in adipocytes is required for lipogenic gene expression, de novo lipogenesis, and lipid desaturation. In addition, adipose tissues rigorously defend Wnt signaling homeostasis under standard nutritional conditions, such that stromal-vascular cells sense and compensate for adipocyte-specific loss. These findings underscore the critical importance of this pathway in adipocyte lipid metabolism and adipose tissue function.
| S-EPMC7554252 | biostudies-literature
Project description:Laminins are heterotrimeric glycoproteins with structural and functional roles in basement membranes. The predominant laminin alpha chain found in adipocyte basement membranes is laminin α4 (LAMA4). Global LAMA4 deletion in mice leads to reduced adiposity and increased energy expenditure, but also results in vascular defects that complicate the interpretation of metabolic data. Here, we describe the generation and initial phenotypic analysis of an adipocyte-specific LAMA4 knockout mouse (Lama4AKO). We first performed an in-silico analysis to determine the degree to which laminin α4 was expressed in human and murine adipocytes. Next, male Lama4AKO and control mice were fed chow or high-fat diets and glucose tolerance was assessed along with serum insulin and leptin levels. Adipocyte area was measured in both epididymal and inguinal white adipose tissue (eWAT and iWAT, respectively), and eWAT was used for RNA-sequencing. We found that laminin α4 was highly expressed in human and murine adipocytes. Further, chow-fed Lama4AKO mice are like control mice in terms of body weight, body composition, and glucose tolerance, although they have larger eWAT adipocytes and lower insulin levels. High-fat-fed Lama4AKO mice are fatter and more glucose tolerant when compared to control mice. Transcriptionally, the eWAT of high-fat fed Lama4AKO mice resembles that of chow-fed control mice. We conclude from these findings that adipocyte-specific LAMA4 deletion is protective in an obesogenic environment, even though overall adiposity is increased.
| S-EPMC9495590 | biostudies-literature
Project description:White adipose tissue (WAT) morphology characterized by hypertrophy (i.e., fewer but larger adipocytes) associates with increased adipose inflammation, lipolysis, insulin resistance, and risk of diabetes. However, the causal relationships and the mechanisms controlling WAT morphology are unclear. Herein, we identified EBF1 as an adipocyte-expressed transcription factor with decreased expression/activity in WAT hypertrophy. In human adipocytes, the regulatory targets of EBF1 were enriched for genes controlling lipolysis and adipocyte morphology/differentiation, and in both humans and murine models, reduced EBF1 levels associated with increased lipolysis and adipose hypertrophy. Although EBF1 did not affect adipose inflammation, TNF? reduced EBF1 gene expression. High-fat diet intervention in Ebf1(+/-) mice resulted in more pronounced WAT hypertrophy and attenuated insulin sensitivity compared with wild-type littermate controls. We conclude that EBF1 is an important regulator of adipose morphology and fat cell lipolysis and may constitute a link between WAT inflammation, altered lipid metabolism, adipose hypertrophy, and insulin resistance.
| S-EPMC4109056 | biostudies-literature
Project description:In mammals, white adipose tissue (WAT) stores and releases lipids, whereas brown adipose tissue (BAT) oxidizes lipids to fuel thermogenesis. In obese individuals, WAT undergoes profound changes; it expands, becomes dysfunctional, and develops a low-grade inflammatory state. Importantly, BAT content and activity decline in obese subjects, mainly as a result of the conversion of brown adipocytes to white-like unilocular cells. Here, we show that BAT "whitening" is induced by multiple factors, including high ambient temperature, leptin receptor deficiency, β-adrenergic signaling impairment, and lipase deficiency, each of which is capable of inducing macrophage infiltration, brown adipocyte death, and crown-like structure (CLS) formation. Brown-to-white conversion and increased CLS formation were most marked in BAT from adipose triglyceride lipase (Atgl)-deficient mice, where, according to transmission electron microscopy, whitened brown adipocytes contained enlarged endoplasmic reticulum, cholesterol crystals, and some degenerating mitochondria, and were surrounded by an increased number of collagen fibrils. Gene expression analysis showed that BAT whitening in Atgl-deficient mice was associated to a strong inflammatory response and NLRP3 inflammasome activation. Altogether, the present findings suggest that converted enlarged brown adipocytes are highly prone to death, which, by promoting inflammation in whitened BAT, may contribute to the typical inflammatory state seen in obesity.
| S-EPMC5928436 | biostudies-literature
Project description:Impaired adipogenesis renders an adipose tissue unable to expand, leading to lipotoxicity and conditions such as diabetes and cardiovascular disease. While factors important for adipogenesis have been studied extensively, those that set the limits of adipose tissue expansion remain undetermined. Feeding a Western-type diet to apolipoprotein E2 knock-in mice, a model of metabolic syndrome, produced 3 groups of equally obese mice: mice with normal glucose tolerance, hyperinsulinemic yet glucose-tolerant mice, and prediabetic mice with impaired glucose tolerance and reduced circulating insulin. Using proteomics, we compared subcutaneous adipose tissues from mice in these groups and found that the expression of PTRF (polymerase I and transcript release factor) associated selectively with their glucose tolerance status. Lentiviral and pharmacologically overexpressed PTRF, whose function is critical for caveola formation, compromised adipocyte differentiation of cultured 3T3-L1cells. In human adipose tissue, PTRF mRNA levels positively correlated with markers of lipolysis and cellular senescence. Furthermore, a negative relationship between telomere length and PTRF mRNA levels was observed in human subcutaneous fat. PTRF is associated with limited adipose tissue expansion underpinning the key role of caveolae in adipocyte regulation. Furthermore, PTRF may be a suitable adipocyte marker for predicting pathological obesity and inform clinical management.
| S-EPMC4101648 | biostudies-literature
Project description:ObjectiveAdipose tissue may contain few large adipocytes (hypertrophy) or many small adipocytes (hyperplasia). We investigated factors of putative importance for adipose tissue morphology.Research design and methodsSubcutaneous adipocyte size and total fat mass were compared in 764 subjects with BMI 18-60 kg/m(2). A morphology value was defined as the difference between the measured adipocyte volume and the expected volume given by a curved-line fit for a given body fat mass and was related to insulin values. In 35 subjects, in vivo adipocyte turnover was measured by exploiting incorporation of atmospheric (14)C into DNA.ResultsOccurrence of hyperplasia (negative morphology value) or hypertrophy (positive morphology value) was independent of sex and body weight but correlated with fasting plasma insulin levels and insulin sensitivity, independent of adipocyte volume (beta-coefficient = 0.3, P < 0.0001). Total adipocyte number and morphology were negatively related (r = -0.66); i.e., the total adipocyte number was greatest in pronounced hyperplasia and smallest in pronounced hypertrophy. The absolute number of new adipocytes generated each year was 70% lower (P < 0.001) in hypertrophy than in hyperplasia, and individual values for adipocyte generation and morphology were strongly related (r = 0.7, P < 0.001). The relative death rate (approximately 10% per year) or mean age of adipocytes (approximately 10 years) was not correlated with morphology.ConclusionsAdipose tissue morphology correlates with insulin measures and is linked to the total adipocyte number independently of sex and body fat level. Low generation rates of adipocytes associate with adipose tissue hypertrophy, whereas high generation rates associate with adipose hyperplasia.
| S-EPMC2797910 | biostudies-literature
Project description:The circadian clock component NR1D1 (REVERBα) is considered a dominant regulator of lipid metabolism, with global Nr1d1 deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (Nr1d1Flox2-6:AdipoqCre), and transcriptional profiling demonstrates that, under basal conditions, direct targets of NR1D1 regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, Nr1d1Flox2-6:AdipoqCre mice do manifest profound obesity, yet without the accompanying WAT inflammation and fibrosis exhibited by controls. Integration of the WAT NR1D1 cistrome with differential gene expression reveals broad control of metabolic processes by NR1D1 which is unmasked in the obese state. Adipocyte NR1D1 does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, NR1D1 action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance.
| S-EPMC8360653 | biostudies-literature
Project description:Intramuscular adipose is conducive to good pork quality, whereas subcutaneous adipose is considered as waste in pig production. So uncovering the regulation differences between these two adiposes is helpful to tissue-specific control of fat deposition. In this study, we found the sensitivity to glucocorticoids (GCs) was lower in intramuscular adipocytes (IMA) compared with subcutaneous adipocytes (SA). Comparison of glucocorticoid receptor (GR) revealed that IMA had lower GR level which contributed to its reduced GCs sensitivity. Higher methylation levels of GR promotor 1-C and 1-H were detected in IMA compared with SA. GR expression decrease was also found in adipocytes when treated with muscle conditioned medium (MCM) in vitro, which resulted in significant inhibition of adipocytes proliferation and differentiation. Since abundant myostatin (MSTN) was detected in MCM by ELISA assay, we further investigated the effect of this myokine on adipocytes. MSTN treatment suppressed adipocytes GR expression, cell proliferation and differentiation, which mimicked the effects of MCM. The methylation levels of GR promotor 1-C and 1-H were also elevated after MSTN treatment. Our study reveals the role of GR in muscle fiber inhibition on intramuscular adipocytes, and identifies myostatin as a muscle-derived modulator for adipose GR level.
| S-EPMC5428816 | biostudies-literature