Body fat distribution is a predictor of metabolic health in obesity. In this Classics in Diabetes article, we revisit a 1985 Diabetes article by Swedish investigators Ohlson et al. This work was one of the first prospective population-based studies that established a relationship between abdominal adiposity and the risk for developing diabetes.
View Article and Find Full Text PDFRecent studies have revealed cellular heterogeneity of mesenchymal stromal cells and immune cells in adipose tissue and emphasized the need for quantitative analysis of small numbers of functionally distinct cells using state-of-the-art "omics" technologies. Here, we present an optimized protocol for precise protein quantification from minute amounts of samples. We describe steps for isolation of mouse adipose progenitor cells, proteomics sample preparation, mass spectrometry measurement, and computational analysis.
View Article and Find Full Text PDFThe G protein-coupled receptor 84 (GPR84), a medium-chain fatty acid receptor, has garnered attention because of its potential involvement in a range of metabolic conditions. However, the precise mechanisms underlying this effect remain elusive. Our study has shed light on the pivotal role of GPR84, revealing its robust expression and functional significance within brown adipose tissue (BAT).
View Article and Find Full Text PDFAdipose tissue exhibits a remarkable capacity to expand, contract, and remodel in response to changes in physiological and environmental conditions. Here, we describe recent advances in our understanding of how functionally distinct tissue-resident mesenchymal stromal cell subpopulations orchestrate several aspects of physiological and pathophysiological adipose tissue remodeling, with a particular focus on the adaptations that occur in response to changes in energy surplus and environmental temperature. The study of adipose tissue remodeling provides a vehicle to understand the functional diversity of stromal cells and offers a lens through which several generalizable aspects of tissue reorganization can be readily observed.
View Article and Find Full Text PDFAdipose tissue exhibits remarkable plasticity with capacity to change in size and cellular composition under physiological and pathophysiological conditions. The emergence of single-cell transcriptomics has rapidly transformed our understanding of the diverse array of cell types and cell states residing in adipose tissues and has provided insight into how transcriptional changes in individual cell types contribute to tissue plasticity. Here, we present a comprehensive overview of the cellular atlas of adipose tissues focusing on the biological insight gained from single-cell and single-nuclei transcriptomics of murine and human adipose tissues.
View Article and Find Full Text PDFMisalignment of feeding rhythms with the light-dark cycle leads to disrupted peripheral circadian clocks and obesity. Conversely, restricting feeding to the active period mitigates metabolic syndrome through mechanisms that remain unknown. We found that genetic enhancement of adipocyte thermogenesis through ablation of the zinc finger protein 423 (ZFP423) attenuated obesity caused by consumption of a high-fat diet during the inactive (light) period by increasing futile creatine cycling in mice.
View Article and Find Full Text PDFObesity is associated with increased cancer incidence and progression. However, the relationship between adiposity and cancer remains poorly understood at the mechanistic level. Here, we report that adipocytes from tumor-invasive mammary fat undergo de-differentiation to fibroblast-like precursor cells during tumor progression and integrate into the tumor microenvironment.
View Article and Find Full Text PDFThe molecular mechanisms underlying obesity-induced increases in β cell mass and the resulting β cell dysfunction need to be elucidated further. Our study revealed that GPR92, expressed in islet macrophages, is modulated by dietary interventions in metabolic tissues. Therefore, we aimed to define the role of GPR92 in islet inflammation by using a high-fat diet-induced (HFD-induced) obese mouse model.
View Article and Find Full Text PDFAdult white adipose tissue (WAT) harbors distinct mesenchymal stromal cell subpopulations that differentially affect WAT function and plasticity. Here we unveil the cellular landscape of the perinatal epididymal WAT primordium using single-cell transcriptomics in male mice. We reveal that adipocyte precursor cells and fibro-inflammatory progenitors (FIPs) emerge as functionally distinct PDGFRβ subpopulations within the epididymal WAT anlagen prior to adipocyte accrual.
View Article and Find Full Text PDFSingle-cell RNA sequencing (scRNA-seq) has revealed that adult white adipose tissue (WAT) harbors functionally diverse subpopulations of mesenchymal stromal cells that differentially impact tissue plasticity. To date, the molecular basis of this cellular heterogeneity has not been fully defined. Here, we describe a multilayered omics approach to dissect adipose progenitor cell heterogeneity in three dimensions: progenitor subpopulation, sex, and anatomical localization.
View Article and Find Full Text PDFEnergy-storing white adipocytes maintain their identity by suppressing the energy-burning thermogenic gene program of brown and beige adipocytes. Here, we reveal that the protein-protein interaction between the transcriptional coregulator ZFP423 and brown fat determination factor EBF2 is essential for restraining the thermogenic phenotype of white adipose tissue (WAT). Disruption of the ZFP423-EBF2 protein interaction through CRISPR-Cas9 gene editing triggers widespread "browning" of WAT in adult mice.
View Article and Find Full Text PDFThe full array of cold-responsive cell types within white adipose tissue that drive thermogenic beige adipocyte biogenesis remains undefined. We demonstrate that acute cold challenge elicits striking transcriptomic changes specifically within DPP4+ PDGFRβ+ adipocyte precursor cells, including a β-adrenergic receptor CREB-mediated induction in the expression of the prothermogenic cytokine, Doxycycline-inducible deletion of in PDGFRβ+ cells at the onset of cold exposure attenuates ILC2 accumulation and beige adipocyte accrual. These studies highlight the multifaceted roles for adipocyte progenitors and the ability of select mesenchymal subpopulations to relay neuronal signals to tissue-resident immune cells in order to regulate tissue plasticity.
View Article and Find Full Text PDFPlasma hyaluronan (HA) increases systemically in type 2 diabetes (T2D) and the HA synthesis inhibitor, 4-Methylumbelliferone, has been proposed to treat the disease. However, HA is also implicated in normal physiology. Therefore, we generated a Hyaluronan Synthase 2 transgenic mouse line, driven by a tet-response element promoter to understand the role of HA in systemic metabolism.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
June 2021
Homeothermic vertebrates produce heat in cold environments through thermogenesis, in which brown adipose tissue (BAT) increases mitochondrial oxidation along with uncoupling of the electron transport chain and activation of uncoupling protein 1 (UCP1). Although the transcription factors regulating the expression of UCP1 and nutrient oxidation genes have been extensively studied, only a few other proteins essential for BAT function have been identified. We describe the discovery of FAM195A, a BAT-enriched RNA binding protein, which is required for cold-dependent thermogenesis in mice.
View Article and Find Full Text PDFAdiponectin is essential for the regulation of tissue substrate utilization and systemic insulin sensitivity. Clinical studies have suggested a positive association of circulating adiponectin with healthspan and lifespan. However, the direct effects of adiponectin on promoting healthspan and lifespan remain unexplored.
View Article and Find Full Text PDFAdipose precursor cells (APCs) exhibit regional variation in response to obesity, for unclear reasons. Here, we reveal that HIFα-induced PDGFRβ signaling within murine white adipose tissue (WAT) PDGFRβ cells drives inhibitory serine 112 (S112) phosphorylation of PPARγ, the master regulator of adipogenesis. Levels of PPARγ S112 phosphorylation in WAT PDGFRβ cells are depot dependent, with levels of PPARγ phosphorylation in PDGFRβ cells inversely correlating with their capacity for adipogenesis upon high-fat-diet feeding.
View Article and Find Full Text PDFThe adipose tissue stroma is a rich source of molecularly distinct stem and progenitor cell populations with diverse functions in metabolic regulation, adipogenesis, and inflammation. The ontology of these populations and the mechanisms that govern their behaviors in response to stimuli, such as overfeeding, however, are unclear. Here, we show that the developmental fates and functional properties of adipose platelet-derived growth factor receptor beta (PDGFRβ)+ progenitor subpopulations are tightly regulated by mitochondrial metabolism.
View Article and Find Full Text PDFChronic low-grade white adipose tissue (WAT) inflammation is a hallmark of metabolic syndrome in obesity. Here, we demonstrate that a subpopulation of mouse WAT perivascular (PDGFRβ) cells, termed fibro-inflammatory progenitors (FIPs), activate proinflammatory signalling cascades shortly after the onset of high-fat diet feeding and regulate proinflammatory macrophage accumulation in WAT in a TLR4-dependent manner. FIPs activation in obesity is mediated by the downregulation of zinc-finger protein 423 (ZFP423), identified here as a transcriptional corepressor of NF-κB.
View Article and Find Full Text PDFThe stromal-vascular fraction (SVF) of white adipose tissue (WAT) is remarkably heterogeneous and consists of numerous cell types that contribute functionally to the expansion and remodeling of WAT in adulthood. A tremendous barrier to studying the implications of this cellular heterogeneity is the inability to readily isolate functionally distinct cell subpopulations from WAT SVF for in vitro and in vivo analyses. Single-cell sequencing technology has recently identified functionally distinct fibro-inflammatory and adipogenic PDGFRβ+ perivascular cell subpopulations in intra-abdominal WAT depots of adult mice.
View Article and Find Full Text PDFAlthough ADP-ribosylation of histones by PARP-1 has been linked to genotoxic stress responses, its role in physiological processes and gene expression has remained elusive. We found that NAD-dependent ADP-ribosylation of histone H2B-Glu35 by small nucleolar RNA (snoRNA)-activated PARP-1 inhibits AMP kinase-mediated phosphorylation of adjacent H2B-Ser36, which is required for the proadipogenic gene expression program. The activity of PARP-1 on H2B requires NMNAT-1, a nuclear NAD synthase, which directs PARP-1 catalytic activity to Glu and Asp residues.
View Article and Find Full Text PDFJ Clin Invest
October 2019
The manner in which white adipose tissue (WAT) expands and remodels directly impacts the risk of developing metabolic syndrome in obesity. Preferential accumulation of visceral WAT is associated with increased risk for insulin resistance, whereas subcutaneous WAT expansion is protective. Moreover, pathologic WAT remodeling, typically characterized by adipocyte hypertrophy, chronic inflammation, and fibrosis, is associated with insulin resistance.
View Article and Find Full Text PDFActivated beige adipocytes have therapeutic potential due to their ability to improve glucose and lipid homeostasis. To date, the origin of beige adipocytes remains enigmatic. Whether beige cells arise through de novo differentiation from resident precursors or through reprogramming of mature white adipocytes has been a topic of intense discussion.
View Article and Find Full Text PDFDermal adipose tissue (also known as dermal white adipose tissue and herein referred to as dWAT) has been the focus of much discussion in recent years. However, dWAT remains poorly characterized. The fate of the mature dermal adipocytes and the origin of the rapidly reappearing dermal adipocytes at different stages remain unclear.
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