Adipocyte‐specific FAK deletion promotes pancreatic β‐cell apoptosis via adipose inflammatory response to exacerbate diabetes mellitus
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ABSTRACT:
SUBMITTER: Ding F
PROVIDER: S-EPMC11208094 | biostudies-literature | 2024 Jun
REPOSITORIES: biostudies-literature
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Project description:Obesity-associated inflammation in white adipose tissue (WAT) is a causal factor of systemic insulin resistance. To better understand how adipocytes regulate WAT inflammation, the present study generated chimeric mice in which inducible 6-phosphofructo-2-kinase was low, normal, or high in WAT while the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3) was normal in hematopoietic cells, and analyzed changes in high-fat diet (HFD)-induced WAT inflammation and systemic insulin resistance in the mice. Indicated by proinflammatory signaling and cytokine expression, the severity of HFD-induced WAT inflammation in WT → Pfkfb3+/- mice, whose Pfkfb3 was disrupted in WAT adipocytes but not hematopoietic cells, was comparable with that in WT → WT mice, whose Pfkfb3 was normal in all cells. In contrast, the severity of HFD-induced WAT inflammation in WT → Adi-Tg mice, whose Pfkfb3 was over-expressed in WAT adipocytes but not hematopoietic cells, remained much lower than that in WT → WT mice. Additionally, HFD-induced insulin resistance was correlated with the status of WAT inflammation and comparable between WT → Pfkfb3+/- mice and WT → WT mice, but was significantly lower in WT → Adi-Tg mice than in WT → WT mice. In vitro, palmitoleate decreased macrophage phosphorylation states of Jnk p46 and Nfkb p65 and potentiated the effect of interleukin 4 on suppressing macrophage proinflammatory activation. Taken together, these results suggest that the Pfkfb3 in adipocytes functions to suppress WAT inflammation. Moreover, the role played by adipocyte Pfkfb3 is attributable to, at least in part, palmitoleate promotion of macrophage anti-inflammatory activation.
| S-EPMC8372836 | biostudies-literature
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 β3 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:BackgroundWNT signaling plays a key role in postnatal bone formation. Individuals with gain-of-function mutations in the WNT co-receptor LRP5 exhibit increased lower-body fat mass and potentially enhanced glucose metabolism, alongside high bone mass. However, the mechanisms by which LRP5 regulates fat distribution and its effects on systemic metabolism remain unclear. This study aims to explore the role of LRP5 in adipose tissue biology and its impact on metabolism.MethodsMetabolic assessments and imaging were conducted on individuals with gain- and loss-of-function LRP5 mutations, along with age- and BMI-matched controls. Mendelian randomization analyses were used to investigate the relationship between bone, fat distribution, and systemic metabolism. Functional studies and RNA sequencing were performed on abdominal and gluteal adipose cells with LRP5 knockdown.ResultsHere we show that LRP5 promotes lower-body fat distribution and enhances systemic and adipocyte insulin sensitivity through cell-autonomous mechanisms, independent of its bone-related functions. LRP5 supports adipose progenitor cell function by activating WNT/β-catenin signaling and preserving valosin-containing protein (VCP)-mediated proteostasis. LRP5 expression in adipose progenitors declines with age, but gain-of-function LRP5 variants protect against age-related fat loss in the lower body.ConclusionsOur findings underscore the critical role of LRP5 in regulating lower-body fat distribution and insulin sensitivity, independent of its effects on bone. Pharmacological activation of LRP5 in adipose tissue may offer a promising strategy to prevent age-related fat redistribution and metabolic disorders.
| S-EPMC11862225 | 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:Phosphatidylcholine (PPC) formula has been therapeutically used to reduce areas of localized fat. However, no single research has been carried out on its effect on a variety of cells in adipose and muscle tissues. Herein, the current study aimed to explore the activity of PPC on different cells in adipose and muscle tissues and to investigate the molecular mechanisms contributing to the effects of PPC on lipolysis and apoptosis. mRNA expression levels of various genes were measured by quantitative real-time PCR. Protein expression levels were observed through Western blotting and cell viability was measured by MTT assay. Lipolysis and caspase 3 activity assay were performed using commercial kits. PPC induces lipolysis and apoptosis in adipocytes (3T3-L1), but not in the other tested cells, including skeletal muscle cells (C2C12 myocytes), endothelial cells (HUVEC), and fibroblasts (BJ). The possible role of TNFα and IL-1β-mediated pathways on the effects of PPC was also revealed. We confirmed that treatment with PPC caused lipolysis and apoptosis in a dose-dependent manner (only in 3T3-L1 adipocytes). The effect of PPC observed in 3T3-L1 adipocytes was not evident in C2C12 myocytes, HUVEC, and fibroblasts. PPC also increased TNFα and IL-1β expression and release in 3T3-L1 adipocytes in a dose-dependent fashion, but not in C2C12 myocytes, HUVEC, and BJ. Suppression of TNFα or IL-1β reversed PPC-induced lipolysis and apoptosis in 3T3-L1 adipocytes, suggesting that PPC could promote adipocyte-specific lipolysis and apoptosis through TNFα and IL-1β-mediated signaling. We conclude that the specific activity of PPC on adipocyte in adipose without other tissue damages can be an effective approach for melting lipid.
| S-EPMC6453443 | biostudies-literature
Project description:Adipocytes are the most abundant cell type in the adipose tissue, and their dysfunction is a significant driver of obesity-related pathologies, such as cancer. The mechanisms that (1) drive the maintenance and secretory activity of adipocytes and (2) mediate the cancer cellular response to the adipocyte-derived factors are not fully understood. To address that gap of knowledge, we investigated how alterations in Src homology region 2-containing protein (SHP2) activity affect adipocyte function and tumor crosstalk. We found that phospho-SHP2 levels are elevated in adipose tissue of obese mice, obese patients, and differentiating adipocytes. Immunofluorescence and immunoprecipitation analyses as well as in-silico protein-protein interaction modeling demonstrated that SHP2 associates with PDHA1, and that a positive association promotes a reactive oxygen species (ROS)-driven adipogenic program. Accordingly, this SHP2-PDHA1-ROS regulatory axis was crucial for adipocyte maintenance and secretion of interleukin-6 (IL-6), a key cancer-promoting cytokine. Mature adipocytes treated with an inhibitor for SHP2, PDHA1, or ROS exhibited an increased level of pro-lipolytic and thermogenic proteins, corresponding to an increased glycerol release, but a suppression of secreted IL-6. A functional analysis of adipocyte-cancer cell crosstalk demonstrated a decreased migration, invasion, and a slight suppression of cell cycling, corresponding to a reduced growth of pancreatic cancer cells exposed to conditioned media (CM) from mature adipocytes previously treated with inhibitors for SHP2/PDHA1/ROS. Importantly, PDAC cell growth stimulation in response to adipocyte CM correlated with PDHA1 induction but was suppressed by a PDHA1 inhibitor. The data point to a novel role for (1) SHP2-PDHA1-ROS in adipocyte maintenance and secretory activity and (2) PDHA1 as a regulator of the pancreatic cancer cells response to adipocyte-derived factors.
| S-EPMC10409927 | biostudies-literature
Project description:Proper regulation of energy storage in adipose tissue is crucial for maintaining insulin sensitivity and molecules contributing to this process have not been fully revealed. Here we show that type II transmembrane protein tenomodulin (TNMD) is upregulated in adipose tissue of insulin-resistant versus insulin-sensitive individuals, who were matched for body mass index (BMI). TNMD expression increases in human preadipocytes during differentiation, whereas silencing TNMD blocks adipogenesis. Upon high-fat diet feeding, transgenic mice overexpressing Tnmd develop increased epididymal white adipose tissue (eWAT) mass, and preadipocytes derived from Tnmd transgenic mice display greater proliferation, consistent with elevated adipogenesis. In Tnmd transgenic mice, lipogenic genes are upregulated in eWAT, as is Ucp1 in brown fat, while liver triglyceride accumulation is attenuated. Despite expanded eWAT, transgenic animals display improved systemic insulin sensitivity, decreased collagen deposition and inflammation in eWAT, and increased insulin stimulation of Akt phosphorylation. Our data suggest that TNMD acts as a protective factor in visceral adipose tissue to alleviate insulin resistance in obesity.
| S-EPMC4757769 | biostudies-literature
Project description:BackgroundDiabetes increases ischemic heart injury via incompletely understood mechanisms. We recently reported that diabetic adipocytes-derived small extracellular vesicles (sEV) exacerbate myocardial reperfusion (MI/R) injury by promoting cardiomyocyte apoptosis. Combining in vitro mechanistic investigation and in vivo proof-concept demonstration, we determined the underlying molecular mechanism responsible for diabetic sEV-induced cardiomyocyte apoptosis after MI/R.Methods and resultsAdult mice were fed a high-fat diet (HFD) for 12 weeks. sEV were isolated from plasma or epididymal adipose tissue. HFD significantly increased the number and size of plasma- and adipocyte-derived sEV. Intramyocardial injection of an equal number of diabetic plasma sEV in nondiabetic hearts significantly increased cardiac apoptosis and exacerbated MI/R-induced cardiac dysfunction. Diabetic plasma sEV significantly activated cardiac caspase 9 but not caspase 8, suggesting that diabetic sEV induces cardiac apoptosis via the mitochondrial pathway. These pathologic alterations were phenotyped by intramyocardial injection of sEV isolated from diabetic adipocytes or HGHL-challenged 3T3L1 adipocytes. To obtain direct evidence that diabetic sEV promotes cardiomyocyte apoptotic cell death, isolated neonatal rat ventricular cardiomyocytes (NRVMs) were treated with sEV and subjected to simulated ischemia/reperfusion (SI/R). Treatment of cardiomyocytes with sEV from diabetic plasma, diabetic adipocytes, or HGHL-challenged 3T3L1 adipocytes significantly enhanced SI/R-induced apoptosis and reduced cell viability. These pathologic effects were replicated by a miR-130b-3p (a molecule increased dramatically in diabetic sEV) mimic and blocked by a miRb-130b-3p inhibitor. Molecular studies identified PGC-1α (i.e. PGC-1α1/-a) as the direct downstream target of miR-130b-3p, whose downregulation causes mitochondrial dysfunction and apoptosis. Finally, treatment with diabetic adipocyte-derived sEV or a miR-130b-3p mimic significantly enhanced mitochondrial reactive oxygen species (ROS) production in SI/R cardiomyocytes. Conversely, treatment with a miR-130b-3p inhibitor or overexpression of PGC-1α extremely attenuated diabetic sEV-induced ROS production.ConclusionWe obtained the first evidence that diabetic sEV promotes oxidative stress and mitochondrial-mediated cardiomyocyte apoptotic cell death, exacerbating MI/R injury. These pathological phenotypes were mediated by miR-130b-3p-induced suppression of PGC-1α expression and subsequent mitochondrial ROS production. Targeting miR-130b-3p mediated cardiomyocyte apoptosis may be a novel strategy for attenuating diabetic exacerbation of MI/R injury.
| S-EPMC11750569 | biostudies-literature
Project description:Aims/hypothesisThe in vivo role of mechanistic target of rapamycin (mTOR) in the development and function of adipose tissue, especially brown adipose tissue (BAT), is not well understood. Here, we aimed to assess the effect of mTOR (also known as Mtor) knockout on adipose tissues and systemic energy metabolism.MethodsWe generated adipocyte-specific mTOR-knockout mice (Adipoq-mTOR) by crossing adiponectin-Cre (Adipoq-Cre) mice with mTOR (flox/flox) mice. The mice were then subjected to morphological, physiological (indirect calorimetry, glucose and insulin tolerance tests) and gene expression analyses to determine the role of mTOR in adipose tissues.ResultsWe provide in vivo evidence that mTOR is essential for adipose tissue development and growth. Deletion of mTOR decreased the mass of both BAT and white adipose tissues (WAT) and induced browning of WAT. In addition, ablation of mTOR in adipose tissues caused insulin resistance and fatty liver in the Adipoq-mTOR mice. Furthermore, mTOR was required for adipocyte differentiation in vivo and activation of PPARγ ameliorated the differentiation deficiency of the mTOR-null adipocytes.Conclusions/interpretationOur findings demonstrate that mTOR is a critical regulator of adipogenesis and systemic energy metabolism. Our study provides key insights into the role of mTOR in adipose tissues; such knowledge may facilitate the development of novel strategies with which to treat obesity and related metabolic diseases.
| S-EPMC5345851 | biostudies-literature
Project description:Background/purposeType 2 diabetes remains a worldwide epidemic with major pathophysiological changes as a result of chronic insulin resistance. Insulin regulates numerous biochemical pathways related to carbohydrate and lipid metabolism.MethodsWe have generated a novel mouse model that allows us to constitutively activate, in an inducible fashion, the distal branch of the insulin signaling transduction pathway specifically in adipocytes.ResultsUsing the adenoviral 36 E4orf1 protein, we chronically stimulate locally the Ras-ERK-MAPK signaling pathway. At the whole body level, this leads to reduced body-weight gain under a high fat diet challenge. Despite overlapping glucose tolerance curves, there is a reduced requirement for insulin action under these conditions. The mice further exhibit reduced circulating adiponectin levels that ultimately lead to impaired lipid clearance, and inflamed and fibrotic white adipose tissues. Nevertheless, they are protected from diet-induced hepatic steatosis. As we observe constitutively elevated p-Akt levels in the adipocytes, even under conditions of low insulin levels, this pinpoints enhanced Ras-ERK-MAPK signaling in transgenic adipocytes as a potential alternative route to bypass proximal insulin signaling events.ConclusionWe conclude that E4orf1 expression in the adipocyte leads to enhanced baseline activation of the distal insulin signaling node, yet impaired insulin receptor stimulation in the presence of insulin, with important implications for the regulation of adiponectin secretion. The resulting systemic phenotype is complex, yet highlights the powerful nature of manipulating selective branches of the insulin signaling network within the adipocyte.
| S-EPMC4588421 | biostudies-literature