-
Molecular Metabolism Mar 2023Dysfunctional, unhealthy expansion of white adipose tissue due to excess dietary intake is a process at the root of obesity and Type 2 Diabetes development. The...
OBJECTIVE
Dysfunctional, unhealthy expansion of white adipose tissue due to excess dietary intake is a process at the root of obesity and Type 2 Diabetes development. The objective of this study is to contribute to a better understanding of the underlying mechanism(s) regulating the early stages of adipose tissue expansion and adaptation to dietary stress due to an acute, high-fat diet (HFD) challenge, with a focus on the communication between adipocytes and other stromal cells.
METHODS
We profiled the early response to high-fat diet exposure in wildtype and adipocyte-specific GPS2-KO (GPS2-AKO) mice at the cellular, tissue and organismal level. A multi-pronged approach was employed to disentangle the complex cellular interactions dictating tissue remodeling, via single-cell RNA sequencing and FACS profiling of the stromal fraction, and semi-quantitative proteomics of the adipocyte-derived exosomal cargo after 5 weeks of HFD feeding.
RESULTS
Our results indicate that loss of GPS2 in mature adipocytes leads to impaired adaptation to the metabolic stress imposed by HFD feeding. GPS2-AKO mice are significantly more inflamed, insulin resistant, and obese, compared to the WT counterparts. At the cellular level, lack of GPS2 in adipocytes impacts upon other stromal populations, with both the eWAT and scWAT depots exhibiting changes in the immune and non-immune compartments that contribute to an increase in inflammatory and anti-adipogenic cell types. Our studies also revealed that adipocyte to stromal cell communication is facilitated by exosomes, and that transcriptional rewiring of the exosomal cargo is crucial for tissue remodeling. Loss of GPS2 results in increased expression of secreted factors promoting a TGFβ-driven fibrotic microenvironment favoring unhealthy tissue remodeling and expansion.
CONCLUSIONS
Adipocytes serve as an intercellular signaling hub, communicating with the stromal compartment via paracrine signaling. Our study highlights the importance of proper regulation of the 'secretome' released by energetically stressed adipocytes at the onset of obesity. Altered transcriptional regulation of factors secreted via adipocyte-derived exosomes (AdExos), in the absence of GPS2, contributes to the establishment of an anti-adipogenic, pro-fibrotic adipose tissue environment, and to hastened progression towards a metabolically dysfunctional phenotype.
Topics: Animals; Mice; Diabetes Mellitus, Type 2; Adipocytes; Obesity; Adipose Tissue; Diet; Fibrosis; Intracellular Signaling Peptides and Proteins
PubMed: 36731652
DOI: 10.1016/j.molmet.2023.101682 -
European Journal of Cell Biology Sep 2023Although phenotypically different, brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) are able to produce heat through non-shivering thermogenesis due...
Although phenotypically different, brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) are able to produce heat through non-shivering thermogenesis due to the presence of mitochondrial uncoupling protein 1 (UCP1). The appearance of thermogenically active beige adipocytes in iWAT is known as browning. Both brown and beige cells originate from mesenchymal stem cells (MSCs), and in culture conditions a browning response can be induced with hypothermia (i.e. 32 °C) during which nuclear leptin immunodetection was observed. The central role of leptin in regulating food intake and energy consumption is well recognised, but its importance in the browning process at the cellular level is unclear. Here, immunocytochemical analysis of MSC-derived adipocytes established nuclear localization of both leptin and leptin receptor suggesting an involvement of the leptin pathway in the browning response. In order to elucidate whether leptin modulates the expression of brown and beige adipocyte markers, BAT and iWAT samples from leptin-deficient (ob/ob) mice were analysed and exhibited reduced brown/beige marker expression compared to wild-type controls. When MSCs were isolated and differentiated into adipocytes, leptin deficiency was observed to induce a white phenotype, especially when incubated at 32 °C. These adaptations were accompanied with morphological signs of impaired adipogenic differentiation. Overall, our results indicate that leptin supports adipocyte browning and suggest a potential role for leptin in adipogenesis and browning.
Topics: Animals; Mice; Adipocytes; Adipocytes, Brown; Adipogenesis; Cell Differentiation; Leptin; Signal Transduction
PubMed: 37467572
DOI: 10.1016/j.ejcb.2023.151342 -
European Journal of Cardio-thoracic... May 2022Properties of the radial artery (RA) have been of immense interest to both laboratory scientists and clinicians, especially due to the increasing utilization of RA as a...
Properties of the radial artery (RA) have been of immense interest to both laboratory scientists and clinicians, especially due to the increasing utilization of RA as a second-choice conduit for coronary artery bypass graft (CABG), after left internal mammary artery.
Topics: Adipocytes; Adipose Tissue; Humans; Radial Artery
PubMed: 35213706
DOI: 10.1093/ejcts/ezac120 -
Adipocyte Dec 2020Although adipose tissue metabolism in obesity has been widely studied, there is limited research on the anorexic state, where the endocrine system is disrupted by... (Review)
Review
Although adipose tissue metabolism in obesity has been widely studied, there is limited research on the anorexic state, where the endocrine system is disrupted by reduced adipose tissue mass and there are depot-specific changes in adipocyte type and function. Stress exposure at different stages of life can alter the balance between energy intake and expenditure and thereby contribute to the pathogenesis of anorexia nervosa. This review integrates information from human clinical trials to describe endocrine, genetic and epigenetic aspects of adipose tissue physiology in the anorexic condition. Changes in the hypothalamus-pituitary-thyroid, -adrenal, and -gonadal axes and their relationships to appetite regulation and adipocyte function are discussed. Because of the role of stress in triggering or magnifying anorexia, and the dynamic but also persistent nature of environmentally-induced epigenetic modifications, epigenetics is likely the link between stress and long-term changes in the endocrine system that disrupt homoeostatic food intake and adipose tissue metabolism. Herein, we focus on the adipocyte and changes in its function, including alterations reinforced by endocrine disturbance and dysfunctional adipokine regulation. This information is critical because of the poor understanding of anorexic pathophysiology, due to the lack of suitable research models, and the complexity of genetic and environmental interactions.
Topics: Adipocytes; Adipose Tissue; Animals; Anorexia; Disease Susceptibility; Endocrine System; Energy Metabolism; Epigenesis, Genetic; Gene Expression Regulation; Humans; Lipid Metabolism; Organ Size; Stress, Physiological
PubMed: 32772766
DOI: 10.1080/21623945.2020.1803643 -
Journal of Molecular Cell Biology Oct 2020The obesity epidemic continues to rise as a global health challenge. Thermogenic brown and beige adipocytes dissipate chemical energy as heat, providing an opportunity... (Review)
Review
The obesity epidemic continues to rise as a global health challenge. Thermogenic brown and beige adipocytes dissipate chemical energy as heat, providing an opportunity for developing new therapeutics for obesity and related metabolic diseases. Anatomically, brown adipose tissue is distributed as discrete depots, while beige adipocytes exist within certain depots of white adipose tissue. Developmentally, brown and beige adipocytes arise from multiple embryonic progenitor populations that are distinct and overlapping. Functionally, they respond to a plethora of stimuli to engage uncoupling protein 1-dependent and independent thermogenic programs, thus improving systemic glucose homeostasis, lipid metabolism, and the clearance of branched-chain amino acids. In this review, we highlight recent advances in our understanding of the molecular and cellular mechanisms that contribute to the developmental and functional heterogeneity of thermogenic adipose tissue.
Topics: Adipocytes; Adipose Tissue; Aging; Animals; Cell Lineage; Humans; Models, Biological; Thermogenesis
PubMed: 32569352
DOI: 10.1093/jmcb/mjaa029 -
Autophagy Dec 2023Macroautophagy/autophagy requires enormous membrane expansions during concerted actions of transient autophagic vesicles and lysosomes, yet the source of the membrane...
Macroautophagy/autophagy requires enormous membrane expansions during concerted actions of transient autophagic vesicles and lysosomes, yet the source of the membrane lipids is poorly understood. Recent work in adipocytes has now pinpointed the de novo lipogenesis pathway as the preferred source of fatty acids for phospholipid in autophagic membrane synthesis, as loss of FASN (fatty acid synthase) disrupts autophagic flux and lysosome function and . These data indicate fatty acid synthesis channels lipid for membrane expansions, whereas fatty acids from circulating lipoproteins provide for adipose lipid storage. Importantly, autophagy blockade upon loss of fatty acids promotes a strong thermogenic phenotype in adipocytes, another striking example whereby autophagy controls cell behavior.
Topics: Fatty Acids; Autophagy; Adipocytes; Lipogenesis; Phospholipids
PubMed: 37602798
DOI: 10.1080/15548627.2023.2246357 -
Pharmacological Research May 2020Adipocyte account for the largest component in breast tissue. Dysfunctional adipocyte metabolism, such as metaflammation in metabolically abnormal obese patients, will... (Review)
Review
Adipocyte account for the largest component in breast tissue. Dysfunctional adipocyte metabolism, such as metaflammation in metabolically abnormal obese patients, will cause hyperplasia and hypertrophy of its constituent adipocytes. Inflamed adipose tissue is one of the biggest risk factors causing breast cancer. Factors linking adipocyte metabolism to breast cancer include dysfunctional secretion of proinflammatory mediators, proangiogenic factors and estrogens. The accumulation of tumor supporting cells and systemic effects, such as insulin resistance, dyslipidemia and oxidative stress, which are caused by abnormal adipocyte metabolism, further contribute to a more aggressive tumor microenvironment and stimulate breast cancer stem cell to influence the development and progression of breast cancer. Here, in this review, we focus on the adipocyte metabolism in regulating breast cancer progression, and discuss the potential targets which can be used for breast cancer therapy.
Topics: Adipocytes; Adipokines; Adipose Tissue; Breast Neoplasms; Disease Progression; Humans; Tumor Microenvironment
PubMed: 32151679
DOI: 10.1016/j.phrs.2020.104741 -
Journal of Lipid Research Feb 2024Adipose tissue is the site of long-term energy storage. During the fasting state, exercise, and cold exposure, the white adipose tissue mobilizes energy for peripheral...
Adipose tissue is the site of long-term energy storage. During the fasting state, exercise, and cold exposure, the white adipose tissue mobilizes energy for peripheral tissues through lipolysis. The mobilization of lipids from white adipose tissue to the liver can lead to excess triglyceride accumulation and fatty liver disease. Although the white adipose tissue is known to release free fatty acids, a comprehensive analysis of lipids mobilized from white adipocytes in vivo has not been completed. In these studies, we provide a comprehensive quantitative analysis of the adipocyte-secreted lipidome and show that there is interorgan crosstalk with liver. Our analysis identifies multiple lipid classes released by adipocytes in response to activation of lipolysis. Time-dependent analysis of the serum lipidome showed that free fatty acids increase within 30 min of β3-adrenergic receptor activation and subsequently decrease, followed by a rise in serum triglycerides, liver triglycerides, and several ceramide species. The triglyceride composition of liver is enriched for linoleic acid despite higher concentrations of palmitate in the blood. To further validate that these findings were a specific consequence of lipolysis, we generated mice with conditional deletion of adipose tissue triglyceride lipase exclusively in adipocytes. This loss of in vivo adipocyte lipolysis prevented the rise in serum free fatty acids and hepatic triglycerides. Furthermore, conditioned media from adipocytes promotes lipid remodeling in hepatocytes with concomitant changes in genes/pathways mediating lipid utilization. Together, these data highlight critical role of adipocyte lipolysis in interorgan crosstalk between adipocytes and liver.
Topics: Mice; Animals; Lipolysis; Fatty Acids, Nonesterified; Lipidomics; Adipocytes; Adipose Tissue; Liver; Triglycerides
PubMed: 37640283
DOI: 10.1016/j.jlr.2023.100434 -
International Journal of Molecular... Feb 2022Adipogenesis is dependent on cytoskeletal remodeling that determines and maintains cellular shape and function. Cytoskeletal proteins contribute to the filament-based...
Adipogenesis is dependent on cytoskeletal remodeling that determines and maintains cellular shape and function. Cytoskeletal proteins contribute to the filament-based network responsible for controlling the shape of adipocytes and promoting the intracellular trafficking of cellular components. Currently, the understanding of these mechanisms and their effect on differentiation and adipocyte function remains incomplete. In this study, we identified the non-muscle myosin 10 (MYH10) as a novel regulator of adipogenesis and adipocyte function through its interaction with the insulin-dependent glucose transporter 4 (GLUT4). MYH10 depletion in preadipocytes resulted in impaired adipogenesis, with knockdown cells exhibiting an absence of morphological alteration and molecular signals. MYH10 was shown in a complex with GLUT4 in adipocytes, an interaction regulated by insulin induction. The missing adipogenic capacity of MYH10 knockdown cells was restored when the cells took up GLUT4 vesicles from neighbor wildtype cells in a co-culture system. This signaling cascade is regulated by the protein kinase C ζ (PKCζ), which interacts with MYH10 to modify the localization and interaction of both GLUT4 and MYH10 in adipocytes. Overall, our study establishes MYH10 as an essential regulator of GLUT4 translocation, affecting both adipogenesis and adipocyte function, highlighting its importance in future cytoskeleton-based studies in adipocytes.
Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Cell Differentiation; Cell Line; Glucose; Glucose Transporter Type 4; Mice; Mice, Inbred C57BL; Myosin Heavy Chains; Myosins; Nonmuscle Myosin Type IIB; Phosphorylation; Protein Kinase C; Signal Transduction
PubMed: 35216482
DOI: 10.3390/ijms23042367 -
Endocrine Journal Jul 2022Adipose tissue is a complex heterogeneous tissue composed of adipocytes along with several non-adipocyte populations, including blood, stromal, endothelial, and... (Review)
Review
Adipose tissue is a complex heterogeneous tissue composed of adipocytes along with several non-adipocyte populations, including blood, stromal, endothelial, and progenitor cells, as well as extracellular matrix (ECM) components. As obesity progresses, the adipose tissue expands dynamically through adipocyte hypertrophy and/or hyperplasia. This expansion requires continuous ECM remodeling to properly accommodate the size increase as well as functional changes. Upon reaching a hypertrophic threshold beyond the adipocyte buffering capacity, excess ECM components are deposited, causing fibrosis and ultimately resulting in unhealthy metabolic maladaptation. These complex ECM remodeling processes in adipose tissues are regulated by the local environment, several key mediators, and genetic factors that are closely linked to insulin sensitivity. It is crucial to understand how adipocytes interact with nonadipocyte populations and various mediators (i.e., immune cells, ECM components, and adipokines) during these processes. This mini-review provides an overview of the latest research into the biology of obesity-induced adipose tissue fibrosis and its related clinical manifestations, providing insight for further studies aimed at controlling metabolic syndrome and its comorbidities.
Topics: Adipocytes; Adipose Tissue; Fibrosis; Humans; Insulin Resistance; Obesity
PubMed: 35675998
DOI: 10.1507/endocrj.EJ22-0035