Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue

AbstractThe proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.

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Phenotyping of Klf14 mouse white adipose tissue enabled by whole slide segmentation with deep neural networks

10.1101/2021.06.03.444997 ◽

2021 ◽

Author(s):

Ramón Casero ◽

Henrik Westerberg ◽

Neil R Horner ◽

Marianne Yon ◽

Alan Aberdeen ◽

...

Keyword(s):

Adipose Tissue ◽

Cell Size ◽

White Adipose Tissue ◽

Linear Models ◽

Spatial Information ◽

Size Analysis ◽

Cell Area ◽

Heterozygous Parent ◽

White Adipocyte ◽

White Adipocytes

White adipose tissue (WAT) plays a central role in metabolism, and multiple diseases and genetic mutations cause its remodeling, most notably obesity, which has reached pandemic levels. WAT is present in subcutaneous (SAT) and visceral (VAT) depots, and its main components are white adipocytes. Quantitative analysis of white adipocyte size and counts is of great interest to understand physiology and disease, due to intra- and inter-depot heterogeneity, as well as better prognosis for hypertrophy than hyperplasia, and for SAT expansion than VAT expansion. H&E histology of whole depot cross-sections provides excellent approximation of cell morphology and preserves spatial information. Previous studies have been limited to window subsampling of whole slides, and cell size analysis. In this paper, we present a deep learning pipeline that can segment overlapping white adipocytes on whole slides and filter out other cells. We also propose a statistical framework based on linear models to study WAT phenotypes with three interconnected levels (body weight BW, depot weight DW and quartile cell area). Applying it to find Klf14 phenotypes in mice using 147 whole slides of WAT H&E histology, we show sexual dimorphism, and different effects between depots, heterozygous parent of origin for the KO allele and genotype (WT vs. Het). In particular, whether variables are correlated (DW vs. BW and cell area vs. DW), and statistical differences between fitted linear models. We also find significant differences between hand-traced or window subsampling datasets and whole slide analysis. Finally, we provide heatmaps of cell size for all the slides, showing substantial spatial heterogeneity and local spatial correlations.

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Noradrenaline and ATP regulate white adipocyte adiponectin exocytosis: disturbed adrenergic and purinergic signalling in obesity-associated diabetes

10.1101/2021.08.19.456508 ◽

2021 ◽

Author(s):

Saliha Musovic ◽

Ali M. Komai ◽

Marina Kalds Said ◽

Yanling Wu ◽

Ingrid Wernstedt Asterholm ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Adrenergic Receptors ◽

Sympathetic Innervation ◽

Sympathetic Nerves ◽

Purinergic Signalling ◽

Diabetic Mice ◽

White Adipocyte ◽

Hmw Adiponectin ◽

Circulating Levels

AbstractWhite adipocyte adiponectin exocytosis is triggered by cAMP and a concomitant increase of cytosolic Ca2+ potentiates its release. White adipose tissue is richly innervated by sympathetic nerves co-releasing noradrenaline (NA) and ATP that may act on receptors in the adipocyte plasma membrane to increase cAMP via adrenergic receptors and Ca2+ via purinergic receptors, respectively. Here we determine the importance of NA and ATP for the regulation of white adipocyte adiponectin exocytosis, at the cellular and molecular level, and we specifically detail the ATP signalling pathway. Immunohistochemical staining demonstrates that tyrosine hydroxylase (enzyme involved in catecholamine synthesis) is dramatically reduced in inguinal white adipose tissue (IWAT) isolated from mice with diet-induced obesity; this is associated with diminished levels of NA in IWAT and with lowered serum adiponectin. Adiponectin exocytosis (measured as increase in plasma membrane capacitance and as secreted product) is triggered by NA or ATP alone in cultured and primary mouse IWAT adipocytes, and enhanced by a combination of the two secretagogues. The ATP-induced adiponectin exocytosis is largely Ca2+-dependent and activated via P2Y2 receptors (P2Y2Rs) and the Gq11/PLC pathway. Adiponectin release induced by the nucleotide is abrogated in adipocytes isolated from obese/diabetic mice and this is associated with ∼70% reduced abundance of P2Y2Rs. The NA-triggered adiponectin exocytosis is likewise abolished in “obese adipocytes”, concomitant with a 50% lower gene expression of beta 3 adrenergic receptors (β3ARs). The NA-stimulated adiponectin secretion does not contain Ca2+-dependent components. Collectively, our data suggest that sympathetic innervation is a principal regulator of adiponectin exocytosis and that disruptions of this control are associated with the obesity-associated reduction of circulating levels of HMW adiponectin.Key point listWhite adipose tissue is richly innervated by sympathetic nerves that co-release noradrenaline (NA) and ATP.Protein levels of tyrosine hydroxylase and NA are dramatically decreased in white adipose tissue from obese/diabetic mice, concomitant with reduced serum levels of high-molecular weight (HMW) adiponectin.NA and ATP stimulate white adipocyte adiponectin exocytosis via beta adrenergic and purinergic receptors respectively. The ATP-induced adiponectin secretion is chiefly Ca2+-dependent and activated via the P2Y2/Gq11/PLC pathway.The purinergic signalling is abrogated in adipocytes from obese/diabetic mice, due to reduced abundance of P2Y2Rs. The response to NA is likewise abolished in “obese adipocytes”, associated with lowered gene expression of beta 3 adrenergic receptors (β3ARs).We propose that sympathetic innervation is central in regulation of adiponectin exocytosis via co-secretion of NA and ATP and that this control is disrupted in obesity-associated diabetes, leading to lower circulating levels of HMW adiponectin.

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Irisin induces white adipose tissue browning in mice as assessed by magnetic resonance imaging

Experimental Biology and Medicine ◽

10.1177/15353702211006049 ◽

2021 ◽

pp. 153537022110060

Author(s):

Yue Chen ◽

Jie Ding ◽

Yufei Zhao ◽

Shenghong Ju ◽

Hui Mao ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Adipose Tissue ◽

Magnetic Resonance ◽

White Adipose Tissue ◽

High Fat Diet ◽

Chow Diet ◽

Resonance Imaging ◽

High Fat ◽

White Adipocytes ◽

Fat Fraction

This study aimed to track and evaluate the effect of low-dose irisin on the browning of white adipose tissue (WAT) in mice using magnetic resonance imaging (MRI) noninvasively in vivo. Mature white adipocytes extracted from mice were cultured, induced and characterized before being treated by irisin. The volume and fat fraction of WAT were quantified using MRI in normal chow diet and high fat mice after injection of irisin. The browning of cultured white adipocytes and WAT in mice were validated by immunohistochemistry and western blotting for uncoupling protein 1 (UCP1) and deiodinase type II (DIO2). The serum indexes were examined with high fat diet after irisin intervention. UCP1 and DIO2 in adipocytes showed increases responding to the irisin treatment. The size of white adipocytes in mice receiving irisin intervention was reduced. MRI measured volumes and fat fraction of WAT were significantly lower after Irisin treatment. Blood glucose and cholesterol levels were reduced in high fat diet mice after irisin treatment. Irisin intervention exerted browning of WAT, resulting reduction of volume and fat fraction of WAT as measured by MRI. Furthermore, it improved the condition of mice with diet-induced obesity and related metabolic disorders.

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Cissus Quadrangularis enhances UCP1 mRNA, indicative of white adipocyte browning and decreases central obesity in humans in a randomized trial

Scientific Reports ◽

10.1038/s41598-021-81606-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Saimai Chatree ◽

Chantacha Sitticharoon ◽

Pailin Maikaew ◽

Kitchaya Pongwattanapakin ◽

Issarawan Keadkraichaiwat ◽

...

Keyword(s):

Treated Group ◽

Dependent Manner ◽

Hip Circumference ◽

White Adipocyte ◽

Ppar Γ ◽

White Adipocytes ◽

Cissus Quadrangularis ◽

Baseline Values ◽

Dose Dependent ◽

Vehicle Treated Group

AbstractObesity is associated with the growth and expansion of adipocytes which could be decreased via several mechanisms. Cissus Quadrangularis (CQ) extract has been shown to reduce obesity in humans; however, its effect on human white adipocytes (hWA) has not been elucidated. This study aimed to investigate the effects of CQ on obesity, lipolysis, and browning of hWA. CQ treatment in obese humans significantly decreased waist circumference at week 4 and week 8 when compared with the baseline values (p < 0.05 all) and significantly decreased hip circumference at week 8 when compared with the baseline and week 4 values (p < 0.05 all). Serum leptin levels of the CQ-treated group were significantly higher at week 8 compared to baseline levels (p < 0.05). In hWA, glycerol release was reduced in the CQ-treated group when compared with the vehicle-treated group. In the browning experiment, pioglitazone, the PPAR-γ agonist, increased UCP1 mRNA when compared to vehicle (p < 0.01). Interestingly, 10, 100, and 1000 ng/ml CQ extract treatment on hWA significantly enhanced UCP1 expression in a dose-dependent manner when compared to pioglitazone treatment (p < 0.001 all). In conclusion, CQ decreased waist and hip circumferences in obese humans and enhanced UCP1 mRNA in hWA suggestive of its action via browning of hWA.

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Contribution of PGC-1α to Obesity- and Caloric Restriction-Related Physiological Changes in White Adipose Tissue

International Journal of Molecular Sciences ◽

10.3390/ijms22116025 ◽

2021 ◽

Vol 22 (11) ◽

pp. 6025

Author(s):

Masaki Kobayashi ◽

Yusuke Deguchi ◽

Yuka Nozaki ◽

Yoshikazu Higami

Keyword(s):

Adipose Tissue ◽

Caloric Restriction ◽

White Adipose Tissue ◽

Mitochondrial Gene ◽

Energy Resource ◽

Peroxisome Proliferator ◽

Physiological Changes ◽

Mitochondrial Gene Expression ◽

Peroxisome Proliferator Activated Receptor ◽

White Adipocytes

Peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) regulates mitochondrial DNA replication and mitochondrial gene expression by interacting with several transcription factors. White adipose tissue (WAT) mainly comprises adipocytes that store triglycerides as an energy resource and secrete adipokines. The characteristics of WAT vary in response to systemic and chronic metabolic alterations, including obesity or caloric restriction. Despite a small amount of mitochondria in white adipocytes, accumulated evidence suggests that mitochondria are strongly related to adipocyte-specific functions, such as adipogenesis and lipogenesis, as well as oxidative metabolism for energy supply. Therefore, PGC-1α is expected to play an important role in WAT. In this review, we provide an overview of the involvement of mitochondria and PGC-1α with obesity- and caloric restriction-related physiological changes in adipocytes and WAT.

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Sympathetic Innervation of White Adipose Tissue: to Beige or Not to Beige?

Physiology ◽

10.1152/physiol.00038.2020 ◽

2021 ◽

Vol 36 (4) ◽

pp. 246-255

Author(s):

Heike Münzberg ◽

Elizabeth Floyd ◽

Ji Suk Chang

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Metabolic Regulation ◽

Current Knowledge ◽

Sympathetic Innervation ◽

Neuronal Circuits ◽

Brown Adipocytes ◽

White Adipocyte ◽

Obesity Research ◽

Neuronal Regulation

Obesity research progresses in understanding neuronal circuits and adipocyte biology to regulate metabolism. However, the interface of neuro-adipocyte interaction is less studied. We summarize the current knowledge of adipose tissue innervation and interaction with adipocytes and emphasize adipocyte transitions from white to brown adipocytes and vice versa. We further highlight emerging concepts for the differential neuronal regulation of brown/beige versus white adipocyte and the interdependence of both for metabolic regulation.

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Pannexin-1 mediated ATP release in adipocytes is sensitive to glucose and insulin and modulates lipolysis and macrophage migration

10.1101/380469 ◽

2018 ◽

Author(s):

Marco Tozzi ◽

Jacob B. Hansen ◽

Ivana Novak

Keyword(s):

Adipose Tissue ◽

Purinergic Receptors ◽

Purinergic Signaling ◽

Cell Metabolism ◽

Atp Release ◽

Extracellular Atp ◽

Adrenergic Stimulation ◽

Pannexin 1 ◽

White Adipocytes ◽

Obesity And Diabetes

One-sentence summaryInsulin inhibits ATP release in adipocytesAbstractExtracellular ATP signaling is involved in many physiological and pathophysiological processes, and purinergic receptors are targets for drug therapy in several diseases, including obesity and diabetes. Adipose tissue has crucial functions in lipid and glucose metabolism and adipocytes express purinergic receptors. However, the sources of extracellular ATP in adipose tissue are not yet characterized.Here, we show that upon adrenergic stimulation white adipocytes release ATP through the pannexin-1 pore that is regulated by a cAMP-PKA dependent pathway. The ATP release correlates with increased cell metabolism, and extracellular ATP induces Ca2+ signaling and lipolysis in adipocytes and promotes macrophages migration. Most importantly, ATP release is markedly inhibited by insulin, and thereby auto/paracrine purinergic signaling in adipose tissue would be attenuated. Furthermore, we define the signaling pathway for insulin regulated ATP release.Our findings reveal the insulin-pannexin-1-purinergic signaling cross-talk in adipose tissue and we propose that deregulation of this signaling may underlie adipose tissue inflammation and type-2 diabetes.

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Role of Arginase 2 in Systemic Metabolic Activity and Adipose Tissue Fatty Acid Metabolism in Diet-Induced Obese Mice

International Journal of Molecular Sciences ◽

10.3390/ijms20061462 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1462 ◽

Cited By ~ 4

Author(s):

Reem Atawia ◽

Haroldo Toque ◽

Mohamed Meghil ◽

Tyler Benson ◽

Nicole Yiew ◽

...

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Normal Diet ◽

Metabolic Dysfunction ◽

Ppar Γ ◽

Obesity And Diabetes ◽

Visceral Adipose ◽

Upregulated Genes

Visceral adipose tissue (VAT) inflammation and metabolic dysregulation are key components of obesity-induced metabolic disease. Upregulated arginase, a ureahydrolase enzyme with two isoforms (A1-cytosolic and A2-mitochondrial), is implicated in pathologies associated with obesity and diabetes. This study examined A2 involvement in obesity-associated metabolic and vascular disorders. WT and globally deleted A2(−/−) or A1(+/−) mice were fed either a high fat/high sucrose (HFHS) diet or normal diet (ND) for 16 weeks. Increases in body and VAT weight of HFHS-fed WT mice were abrogated in A2−/−, but not A1+/−, mice. Additionally, A2−/− HFHS-fed mice exhibited higher energy expenditure, lower blood glucose, and insulin levels compared to WT HFHS mice. VAT and adipocytes from WT HFHS fed mice showed greater A2 expression and adipocyte size and reduced expression of PGC-1α, PPAR-γ, and adiponectin. A2 deletion blunted these effects, increased levels of active AMPK-α, and upregulated genes involved in fatty acid metabolism. A2 deletion prevented HFHS-induced VAT collagen deposition and inflammation, which are involved in adipocyte metabolic dysfunction. Endothelium-dependent vasorelaxation, impaired by HFHS diet, was significantly preserved in A2−/− mice, but more prominently maintained in A1+/− mice. In summary, A2 is critically involved in HFHS-induced VAT inflammation and metabolic dysfunction.

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Adipokines: inflammation and the pleiotropic role of white adipose tissue

British Journal Of Nutrition ◽

10.1079/bjn20041213 ◽

2004 ◽

Vol 92 (3) ◽

pp. 347-355 ◽

Cited By ~ 1305

Author(s):

Paul Trayhurn ◽

I. Stuart Wood

Keyword(s):

Adipose Tissue ◽

Growth Factor ◽

Inflammatory Cytokines ◽

Acute Phase ◽

White Adipose Tissue ◽

Acute Phase Proteins ◽

Endocrine Function ◽

Low Grade ◽

Circulating Levels

White adipose tissue is now recognised to be a multifunctional organ; in addition to the central role of lipid storage, it has a major endocrine function secreting several hormones, notably leptin and adiponectin, and a diverse range of other protein factors. These various protein signals have been given the collective name ‘adipocytokines’ or ‘adipokines’. However, since most are neither ‘cytokines’ nor ‘cytokine-like’, it is recommended that the term ‘adipokine’ be universally adopted to describe a protein that is secreted from (and synthesised by) adipocytes. It is suggested that the term is restricted to proteins secreted from adipocytes, excluding signals released only by the other cell types (such as macrophages) in adipose tissue. Theadipokinome(which together with lipid moieties released, such as fatty acids and prostaglandins, constitute thesecretomeof fat cells) includes proteins involved in lipid metabolism, insulin sensitivity, the alternative complement system, vascular haemostasis, blood pressure regulation and angiogenesis, as well as the regulation of energy balance. In addition, there is a growing list of adipokines involved in inflammation (TNFα, IL-1β, IL-6, IL-8, IL-10, transforming growth factor-β, nerve growth factor) and the acute-phase response (plasminogen activator inhibitor-1, haptoglobin, serum amyloid A). Production of these proteins by adipose tissue is increased in obesity, and raised circulating levels of several acute-phase proteins and inflammatory cytokines has led to the view that the obese are characterised by a state of chronic low-grade inflammation, and that this links causally to insulin resistance and the metabolic syndrome. It is, however, unclear as to the extent to which adipose tissue contributes quantitatively to the elevated circulating levels of these factors in obesity and whether there is a generalised or local state of inflammation. The parsimonious view is that the increased production of inflammatory cytokines and acute-phase proteins by adipose tissue in obesity relates primarily to localised events within the expanding fat depots. It is suggested that these events reflect hypoxia in parts of the growing adipose tissue mass in advance of angiogenesis, and involve the key controller of the cellular response to hypoxia, the transcription factor hypoxia inducible factor-1.

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