Adipose Tissue Hypoxia Research Articles

Hypoxia signaling in the adipose tissue.

Obesity per se is rapidly emerging all over the planet and further accounts for many other life-threatening conditions, such as diabetes, cardiovascular diseases, and cancers. Decreased oxygen supply or increased relative oxygen consumption in the adipose tissue results in adipose tissue hypoxia, which is a hallmark of obesity. This review aims to provide an up-to-date overview of the hypoxia signaling in the adipose tissue. First, we summarize literature evidence to demonstrate that hypoxia is regularly observed during adipose tissue remodeling in human and rodent models of obesity. Next, we discuss how hypoxia-inducible factors (HIFs) are regulated and how adipose tissues behave in response to hypoxia. Then, the differential roles of adipose HIF-1α and HIF-2α in adipose tissue biology and obesity pathology are highlighted. Finally, the review emphasizes the importance of modulating adipose hypoxia as a therapeutic avenue to assist adipose tissues in functionally adapting to hypoxic conditions, ultimately promoting adipose health and improving outcomes due to obesity.

Hypoxia in Human Obesity: New Insights from Inflammation towards Insulin Resistance-A Narrative Review.

Insulin resistance (IR), marked by reduced cellular responsiveness to insulin, and obesity, defined by the excessive accumulation of adipose tissue, are two intertwined conditions that significantly contribute to the global burden of cardiometabolic diseases. Adipose tissue, beyond merely storing triglycerides, acts as an active producer of biomolecules. In obesity, as adipose tissue undergoes hypertrophy, it becomes dysfunctional, altering the release of adipocyte-derived factors, known as adipokines. This dysfunction promotes low-grade chronic inflammation, exacerbates IR, and creates a hyperglycemic, proatherogenic, and prothrombotic environment. However, the fundamental cause of these phenomena remains unclear. This narrative review points to hypoxia as a critical trigger for the molecular changes associated with fat accumulation, particularly within visceral adipose tissue (VAT). The activation of hypoxia-inducible factor-1 (HIF-1), a transcription factor that regulates homeostatic responses to low oxygen levels, initiates a series of molecular events in VAT, leading to the aberrant release of adipokines, many of which are still unexplored, and potentially affecting peripheral insulin sensitivity. Recent discoveries have highlighted the role of hypoxia and miRNA-128 in regulating the insulin receptor in visceral adipocytes, contributing to their dysfunctional behavior, including impaired glucose uptake. Understanding the complex interplay between adipose tissue hypoxia, dysfunction, inflammation, and IR in obesity is essential for developing innovative, targeted therapeutic strategies.

Enhancing adipose tissue functionality in obesity: senotherapeutics, autophagy and cellular senescence as a target.

Obesity, a global health crisis, disrupts multiple systemic processes, contributing to a cascade of metabolic dysfunctions by promoting the pathological expansion of visceral adipose tissue (VAT). This expansion is characterized by impaired differentiation of pre-adipocytes and an increase in senescent cells, leading to a pro-inflammatory state and exacerbated oxidative stress. Particularly, the senescence-associated secretory phenotype (SASP) and adipose tissue hypoxia further impair cellular function, promoting chronic disease development. This review delves into the potential of autophagy modulation and the therapeutic application of senolytics and senomorphics as novel strategies to mitigate adipose tissue senescence. By exploring the intricate mechanisms underlying adipocyte dysfunction and the emerging role of natural compounds in senescence modulation, we underscore the promising horizon of senotherapeutics in restoring adipose health. This approach not only offers a pathway to combat the metabolic complications of obesity, but also opens new avenues for enhancing life quality and managing the global burden of obesity-related conditions. Our analysis aims to bridge the gap between current scientific progress and clinical application, offering new perspectives on preventing and treating obesity-induced adipose dysfunction.

Comparative proteomic analysis of pathological characterization of adipose tissue remodeling induced by high-fat diet and high-carbohydrate diet in grass carp (Ctenopharyngodon idellus)

Our previous research found that excessive accumulation of adipose tissue is an important factor that reduces fish tolerance and utilization of high-energy feeds and limits the development of high-energy feeds in the aquaculture industry. However, the pathological characteristics and molecular mechanisms of fish adipose tissue remodeling caused by high-energy diet were still unclear. In this study, using histopathological observation, we found that restricted adipocyte hyperplasia, adipocyte hypertrophy, inflammation, and fibrosis are the main characteristics of pathological remodeling of fish adipose tissue induced by high-fat diet (HFD) and high-carbohydrate diet (HCD). Besides, this study further analyzed the molecular mechanisms and key marker proteins invovled in pathological remodeling of adipose tissue induced by HFD and HCD through comparative proteomics. The results found: (1) Inhibition of the differentiation of preadipocytes may be the main pathway through which both HCD and HFD inhibited adipocyte hyperplasia in grass carp; (2) Although both HFD and HCD induce adipocyte hypertrophy by increasing the de novo lipogenesis (DNL) pathway and promoting triglycerides (TG) synthesis. But the difference is that HFD increases fatty acid transport, while HCD increases glycolysis; (3) The inhibitory effect of HCD on glucose transporter type 4 (Glut4) may be an important cause of carbohydrate intolerance in fish; (4) Both HFD and HCD increase lactate production by promoting the expression of lactate dehydrogenase (Ldh), which may be the molecular mechanism of high-energy diet-induced adipose tissue hypoxia; (5) Interleukin-8 (Il-8) can be used as a pro-inflammatory marker for identifying HFD and HCD induced adipose tissue inflammation. This study aims to incestigate the reasons why HFD and HCD have negative effects on fish from the perspective of pathological remodeling of adipose tissue, and provide new underlying regulatory targets for improving the tolerance and utilization of HCD or HFD in farmed fish.

Limited oxygen in standard cell culture alters metabolism and function of differentiated cells

The in vitro oxygen microenvironment profoundly affects the capacity of cell cultures to model physiological and pathophysiological states. Cell culture is often considered to be hyperoxic, but pericellular oxygen levels, which are affected by oxygen diffusivity and consumption, are rarely reported. Here, we provide evidence that several cell types in culture actually experience local hypoxia, with important implications for cell metabolism and function. We focused initially on adipocytes, as adipose tissue hypoxia is frequently observed in obesity and precedes diminished adipocyte function. Under standard conditions, cultured adipocytes are highly glycolytic and exhibit a transcriptional profile indicative of physiological hypoxia. Increasing pericellular oxygen diverted glucose flux toward mitochondria, lowered HIF1α activity, and resulted in widespread transcriptional rewiring. Functionally, adipocytes increased adipokine secretion and sensitivity to insulin and lipolytic stimuli, recapitulating a healthier adipocyte model. The functional benefits of increasing pericellular oxygen were also observed in macrophages, hPSC-derived hepatocytes and cardiac organoids. Our findings demonstrate that oxygen is limiting in many terminally-differentiated cell types, and that considering pericellular oxygen improves the quality, reproducibility and translatability of culture models.

Adipose Tissue Hypoxia in Obesity: Clinical Reappraisal of Hypoxia Hypothesis.

Obese subjects exhibit lower adipose tissue oxygen consumption in accordance with the lower adipose tissue blood flow. Thereby, compared to lean subjects, obese individuals have almost half lower capillary density and more than half lower vascular endothelial growth factor (VEGF). The VEGF expression together with hypoxia-inducible transcription factor-1 alpha (HIF-1α) activity also requires phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR)-mediated signaling. Especially HIF-1α is an important signaling molecule for hypoxia to induce the inflammatory responses. Hypoxia contributes to several biological functions, such as angiogenesis, cell proliferation, apoptosis, inflammation, and insulin resistance (IR). Pathogenesis of obesity-related comorbidities is attributed to intermittent hypoxia (IH), which is mostly observed in visceral obesity. Proinflammatory phenotype of the adipose tissue is a crucial link between IH and the development of IR. Inhibition of adaptive unfolded protein response (UPR) in hypoxia increases β cell death. Moreover, deletion of HIF-1α worsens β cell function. Oxidative stress, as well as the release of proinflammatory cytokines/adipokines in obesity, is proportional to the severity of IH. Reactive oxygen species (ROS) generation at mitochondria is responsible for propagation of the hypoxic signal; however, mitochondrial ROS production is required for hypoxic HIF-1α protein stabilization. Alterations in oxygen availability of adipose tissue directly affect the macrophage polarization and are responsible for the dysregulated adipocytokines production in obesity. Hypoxia both inhibits adipocyte differentiation from preadipocytes and macrophage migration from the hypoxic adipose tissue. Upon reaching a hypertrophic threshold beyond the adipocyte fat loading capacity, excess extracellular matrix (ECM) components are deposited, causing fibrosis. HIF-1α initiates the whole pathological process of fibrosis and inflammation in the obese adipose tissue. In addition to stressed adipocytes, hypoxia contributes to immune cell migration and activation which further aggravates adipose tissue fibrosis. Therefore, targeting HIF-1α might be an efficient way to suppress hypoxia-induced pathological changes in the ECM. The fibrosis score of adipose tissue correlates negatively with the body mass index and metabolic parameters. Inducers of browning/beiging adipocytes and adipokines, as well as modulations of matrix remodeling enzyme inhibitors, and associated gene regulators, are potential pharmacological targets for treating obesity.

Lipid Storage, Lipolysis, and Lipotoxicity in Obesity.

The ratio of free fatty acid (FFA) turnover decreases significantly with the expansion of white adipose tissue. Adipose tissue and dietary saturated fatty acid levels significantly correlate with an increase in fat cell size and number. The G0/G1 switch gene 2 increases lipid content in adipocytes and promotes adipocyte hypertrophy through the restriction of triglyceride (triacylglycerol: TAG) turnover. Hypoxia in obese adipose tissue due to hypertrophic adipocytes results in excess deposition of extracellular matrix (ECM) components. Cluster of differentiation (CD) 44, as the main receptor of the extracellular matrix component regulates cell-cell and cell-matrix interactions including diet-induced insulin resistance. Excess TAGs, sterols, and sterol esters are surrounded by the phospholipid monolayer surface and form lipid droplets (LDs). Once LDs are formed, they grow up because of the excessive amount of intracellular FFA stored and reach a final size. The ratio of FFA turnover/lipolysis decreases significantly with increases in the degree of obesity. Dysfunctional adipose tissue is unable to expand further to store excess dietary lipids, increased fluxes of plasma FFAs lead to ectopic fatty acid deposition and lipotoxicity. Reduced neo-adipogenesis and dysfunctional lipid-overloaded adipocytes are hallmarks of hypertrophic obesity linked to insulin resistance. Obesity-associated adipocyte death exhibits feature of necrosis-like programmed cell death. Adipocyte death is a prerequisite for the transition from hypertrophic to hyperplastic obesity. Increased adipocyte number in obesity has life-long effects on white adipose tissue mass. The positive correlation between the adipose tissue volume and magnetic resonance imaging proton density fat fraction estimation is used for characterization of the obesity phenotype, as well as the risk stratification and selection of appropriate treatment strategies. In obese patients with type 2 diabetes, visceral adipocytes exposed to chronic/intermittent hyperglycemia develop a new microRNAs' (miRNAs') expression pattern. Visceral preadipocytes memorize the effect of hyperglycemia via changes in miRNAs' expression profile and contribute to the progression of diabetic phenotype. Nonsteroidal anti-inflammatory drugs, metformin, and statins can be beneficial in treating the local or systemic consequences of white adipose tissue inflammation. Rapamycin inhibits leptin-induced LD formation. Collectively, in this chapter, the concept of adipose tissue remodeling in response to adipocyte death or adipogenesis, and the complexity of LD interactions with the other cellular organelles are reviewed. Furthermore, clinical perspective of fat cell turnover in obesity is also debated.

The role of adipose tissue and subsequent liver tissue hypoxia in obesity and early stage metabolic dysfunction associated steatotic liver disease.

Obesity is linked to several health complication, including Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD). Adipose tissue hypoxia has been suggested as an important player in the pathophysiological mechanism leading to chronic inflammation in obesity, and in the progression of MASLD. The study aims to investigate the effect of progressive obesity on adipose and liver tissue hypoxia. Male 8-week-old C57BL/6J mice were fed a high-fat high-fructose diet (HFHFD) or control diet (CD) for 4, 8, 12, 16 and 20 weeks. Serum ALT, AST and lipid levels were determined, and glucose and insulin tolerance testing was performed. Liver, gonadal and subcutaneous adipose tissue was assessed histologically. In vivo tissue pO2 measurements were performed in gonadal adipose tissue and liver under anesthesia. A PCR array for hypoxia responsive genes was performed in liver and adipose tissue. The main findings in the liver were validated in another diet-induced MASLD mice model, the choline-deficient L-amino acid defined high-fat diet (CDAHFD). HFHFD feeding induced a progressive obesity, dyslipidaemia, insulin resistance and MASLD. In vivo pO2 was decreased in gonadal adipose tissue after 8 weeks of HFHFD compared to CD, and decreased further until 20 weeks. Liver pO2 was only significantly decreased after 16 and 20 weeks of HFHFD. Gene expression and histology confirmed the presence of hypoxia in liver and adipose tissue. Hypoxia could not be confirmed in mice fed a CDAHFD. Diet-induced obesity in mice is associated with hypoxia in liver and adipose tissue. Adipose tissue hypoxia develops early in obesity, while liver hypoxia occurs later in the obesity development but still within the early stages of MASLD. Liver hypoxia could not be directly confirmed in a non-obese liver-only MASLD mice model, indicating that obesity-related processes such as adipose tissue hypoxia are important in the pathophysiology of obesity and MASLD.

Myricetin attenuates hypoxia-induced inflammation in human adipocytes.

Adipose tissue hypoxia plays a crucial role in the development of chronic low-grade systemic inflammation which has been associated with the pathogenesis of obesity-related diseases. Myricetin is a natural compound present in numerous plant-based foods with presumed anti-inflammatory and beneficial health effects. The impact of this flavonoid on hypoxia-induced expression of inflammatory adipokines and hypoxia-regulated pathways is unknown so far and has been addressed in the present study. Differentiated human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were cultured with or without myricetin under normoxic and hypoxic conditions for varying time periods. The effect of hypoxia and myricetin on the expression of the investigated adipokines was measured by real-time RT-PCR. Western blot analysis was used for the detection of transcription factors involved in hypoxia-regulated pathways. Myricetin interfered in the hypoxia-induced regulation of adipokines and the underlying pathways, which are involved in transmitting the inflammatory response. It strongly repressed hypoxia-induced expression of apelin, leptin, chemerin, asprosin, and DPP-4 and HIF-1α accumulation in the nucleus was diminished. Furthermore, the activation of the key regulators in the inflammatory response NF-κB, Akt, and CREB was suppressed by myricetin under hypoxic conditions. Myricetin also decreased hypoxia-induced accumulation of the pro-tumorigenic transcription factors Snail and Slug in the nucleus. Taken together, our results indicated that myricetin regulated hypoxia-induced expression of adipokines and hypoxia-regulated pathways in human adipocytes. Our study therefore provided evidence of the anti-inflammatory effects of myricetin in hypoxia-treated human adipocytes.

Does Insulin Resistance Contribute to Neuroinflammation, Cognitive Decline and Brain Senescence in Obesity?

The burgeoning prevalence of obesity and overweight conditions from the age of adolescence and throughout the lifespan has reached epidemic proportions in industrialized nations throughout the globe. The development of insulin resistance is one of the most common observations in obesity and is associated with a systemic hypoxia in adipose tissue and a chronic inflammatory state. The insulin resistance affects multiple elements of substrate oxidation and oxidative free radical generation in both somatic and neural tissues and with cytokine-linked chronic inflammation likely originating in adipose tissue depots. In studies with aging congenic lean and obese rats chronic hyperinsulinemia and brain shrinkage has now been reported, albeit it in the absence of Type 2 diabetes (NIDDM), hypertension (HTN) or other comorbidities, thereby suggesting that aspects of disordered substrate metabolism including insulin resistance as commonly observed in obesity may be a key contributory factor in the development of a neuroinflammatory linked brain shrinkage with accompanying decreases in brain mass, protein and DNA content, and which were further compromised when fed an isocaloric high vs. a low glycemic insulinogenic diet containing sucrose vs. cornstarch respectively. These results suggest that chronic insulin resistance of obesity secondary at least in part to dietary factors represents a likely independent risk factor in the progression of neuroinflammation, DNA damage, brain shrinkage and neural senescence in this strain of obese rats.

Nicotinamide mononucleotide attenuates HIF-1α activation and fibrosis in hypoxic adipose tissue via NAD+/SIRT1 axis.

Fibrosis is increasingly considered as a major contributor in adipose tissue dysfunction. Hypoxic activation of hypoxia-inducible factor 1α (HIF-1α) induces a profibrotic transcription, leading to adipose fibrosis. Nicotinamide mononucleotide (NMN), a member of the vitamin B3 family, has been shown to relieve hepatic and cardiac fibrosis, but its effects on hypoxic adipose fibrosis and the underlying mechanism remain unclear. We aimed to elucidate the roles of NMN in regulating HIF-1α and fibrosis in hypoxic adipose tissue. Mice were placed in a hypobaric chamber for four weeks to induce adipose fibrosis. NMN (500 mg/kg, every three days) was administered by intraperitoneal injection. In vitro, Stromal vascular fractions (SVF) cells were treated by hypoxia with or without NMN (200μM), sirtinol (25μM, a SIRT1 inhibitor) and CoCl2 (100μM, a HIF1α enhancer). The effects of NMN on hypoxia-associated adipose fibrosis, inflammation, NAD+/SIRT1 axis alteration, and HIF-1α activation were evaluated by real-time polymerase chain reaction (PCR), western blots, immunohistochemistry staining, immunoprecipitation, and assay kits. Mice placed in a hypoxic chamber for four weeks showed obvious adipose fibrosis and inflammation, which were attenuated by NMN. NMN also restore the compromised NAD+/SIRT1 axis and inhibited the activation of HIF-1α induced by hypoxia. In hypoxia-induced SVFs, the SIRT1 inhibitor sirtinol blocked the anti-fibrotic and anti-inflammatory effects of NMN, upregulated the HIF-1α and its acetylation level. The HIF1α stabilizer CoCl2 showed similar effects as sirtinol. NMN effectively attenuated HIF-1α activation-induced adipose fibrosis and inflammation by restoring the compromised NAD+/SIRT1 axis.

Destabilization of HIF-1a by Diabetes, Oxidative Stress, Obesity and Other Related Disorders

One of the most fundamental molecular processes in response to hypoxia is the activation and stabilization of a transcriptional factor called hypoxia induced factor 1a (HIF-1a), which is responsible for the regulation of many downstream effector genes. Multiple key biological pathways such as proliferation, energy metabolism, invasion, and metastasis are governed by these genes. This article discusses the role of hypoxia-inducible factor 1a (HIF-1a) in metabolic and pathological processes, particularly in adipose tissue, oxidative stress, inflammation, diabetes and cancer. HIF1A is a basic helix-loophelix PAS domain containing protein, and is considered as the master transcriptional regulator of cellular and developmental response to hypoxia. HIF-1a regulates the expression of genes involved in angiogenesis, glucose metabolism, inflammation and oxidative stress. In obesity, adipose tissue hypoxia leads to increased expression of HIF-1a, which can lead to chronic inflammation and adipose tissue dysfunction. Another field that HIF-1a is also involved in cancer pathogenesis pathways, such as proliferation, invasion, angiogenesis, and metastasis, and is considered a potential therapeutic target for metabolic/genetic diseases and cancer. Direct and indirect HIF-1 inhibitors have been identified, but only a few have entered clinical trials due to their multiple side effects.

Abstract 9464: Adipocyte-Derived Fatty-Acid-Binding Protein 4 Impairs Human Dermal Microvascular Endothelial Cells Under Hypoxia Insults - A Mechanistic Clue to Impaired Wound Healing in Obesity

Introduction: Dermal white adipose tissue is found in the dermis of the skin, which may participate in the wound healing process. Obesity-mediated adipocyte hypertrophy has been related to adipose tissue hypoxia and chronic low-grade inflammation, which may impair wound healing by suppressing the vascularity. Fatty-acid-binding protein (FABP) 4 is a cytosolic fatty acid chaperone expressed in adipocytes, which may be involved in the pathogenesis of some vascular diseases and was found upregulated in skin tissue of obese animals. This study aimed to investigate the potential mechanistic impacts of adipocyte-derived FABP4 on vascular cells for wound healing under hypoxia insults. Methods and Results: Primary human dermal microvascular endothelial cells (HDMECs) and adipocytes were used. FABP4 and inflammatory protein expressions such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β were upregulated under the hypoxic conditions. Treatment with conditioned medium from adipocytes under the hypoxic conditions significantly impaired cell function including migration and tube formation abilities in HDMECs. Furthermore, FABP4 and inflammatory protein expressions were upregulated, and angiogenic signaling pathways such as phospho-AKT/hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF)/ stromal cell-derived factor (SDF)-1 were downregulated in these conditioned medium treated HDMECs. Interestingly, administration of FABP4 inhibitor could reverse the conditioned medium-induced cell damages in HDMECs. On the other hand, FABP4 could directly impair cell functions with lower angiogenic and higher inflammatory protein expressions in HDMECs under the hypoxic conditions. Conclusions: Our pilot findings suggested that adipocyte hypoxia might lead to the secretion of inflammatory proteins and FABP4. Adipocyte-derived FABP4 could impair the migration and tube formation abilities of HDMECs via upregulating TNF-α/IL-6/IL-1β and downregulating phospho-AKT/HIF-1α/VEGF/SDF-1 signal pathways. Our findings provide a theoretical basis to the potential impact of FABP4 as a novel therapeutic target on wound healing in obese subjects with adipose tissue hypoxia.

Metabolic Syndrome Ameliorated by 4-Methylesculetin by Reducing Hepatic Lipid Accumulation

Obesity is a chronic metabolic disease caused by an imbalance between energy intake and expenditure during a long period and is characterized by adipose tissue disfunction and hepatic steatosis. The aim of this study was to investigate the effect of 4-methylesculetin (4-ME), a coumarin derivative, upon adipose microenvironment and hepatic steatosis in mice induced by a high-fat diet (HFD), and to explore potential mechanisms of its beneficial effect on metabolic disorders. HFD-fed mice displayed visceral obesity, insulin resistance, and hepatic lipid accumulation, which was remarkably ameliorated by 4-ME treatment. Meanwhile, 4-ME ameliorated adipocyte hypertrophy, macrophage infiltration, hypoxia, and fibrosis in epididymal adipose tissue, thus improving the adipose tissue microenvironment. Furthermore, 4-ME reversed the increase in CD36, PPAR-γ, SREBP-1, and FASN, and the decrease in CPT-1A, PPAR-α, and Nrf2 translocation into the nucleus in livers of HFD mice and in FFA-incubated hepatocytes. Moreover, the beneficial effects of 4-ME upon lipid deposition and the expression of proteins related to lipid metabolism in FFA-induced LO2 cells were abolished by ML385, a specific Nrf2 inhibitor, indicating that Nrf2 is necessary for 4-ME to reduce hepatic lipid deposition. These findings suggested that 4-ME might be a potential lead compound candidate for preventing obesity and MAFLD.

MicroRNA-29 Ameliorates Fibro-Inflammation and Insulin Resistance in HIF1α-Deficient Obese Adipose Tissue by Inhibiting Endotrophin Generation.

Dysregulation of extracellular matrix proteins in obese adipose tissue (AT) induces systemic insulin resistance. The metabolic roles of type VI collagen and its cleavage peptide endotrophin in obese AT are well established. However, the mechanisms regulating endotrophin generation remain elusive. Herein, we identified that several endotrophin-containing peptides (pre-endotrophins) were generated from the COL6A3 chain in a stepwise manner for the efficient production of mature endotrophin, partly through the action of hypoxia-induced matrix metalloproteinases (MMPs), including MMP2, MMP9, and MMP16. Hypoxia is an upstream regulator of COL6A3 expression and the proteolytic processing that regulates endotrophin generation. Hypoxia-inducible factor 1α (HIF1α) and the hypoxia-associated suppression of microRNA-29 (miR-29) cooperatively control the levels of COL6A3 and MMPs, which are responsible for endotrophin generation in hypoxic ATs. Adipocyte-specific Hif1α knock-out (APN-HIF1αKO) mice fed a chronic high-fat diet exhibited the significant amelioration of both local fibro-inflammation in AT and systemic insulin resistance compared with their control littermates, partly through the inhibition of endotrophin generation. Strikingly, adenovirus-mediated miR-29 overexpression in the ATs of APN-HIF1αKO mice in obesity significantly decreased endotrophin levels, suggesting that miR-29, combined with HIF1α inhibition in AT, could be a promising therapeutic strategy for treating obesity and related metabolic diseases.

Inhibition of Adipose Tissue Beiging by HIV Integrase Inhibitors, Dolutegravir and Bictegravir, Is Associated with Adipocyte Hypertrophy, Hypoxia, Elevated Fibrosis, and Insulin Resistance in Simian Adipose Tissue and Human Adipocytes.

For people living with HIV, treatment with integrase-strand-transfer-inhibitors (INSTIs) can promote adipose tissue (AT) gain. We previously demonstrated that INSTIs can induce hypertrophy and fibrosis in AT of macaques and humans. By promoting energy expenditure, the emergence of beige adipocytes in white AT (beiging) could play an important role by limiting excess lipid storage and associated adipocyte dysfunction. We hypothesized that INSTIs could alter AT via beiging inhibition. Fibrosis and gene expression were measured in subcutaneous (SCAT) and visceral AT (VAT) from SIV-infected, dolutegravir-treated (SIVART) macaques. Beiging capacity was assessed in human adipose stromal cells (ASCs) undergoing differentiation and being exposed to dolutegravir, bictegravir, or raltegravir. Expression of beige markers, such as positive-regulatory-domain-containing-16 (PRDM16), were lower in AT of SIVART as compared to control macaques, whereas fibrosis-related genes were higher. Dolutegravir and bictegravir inhibited beige differentiation in ASCs, as shown by lower expression of beige markers and lower cell respiration. INSTIs also induced a hypertrophic insulin-resistant state associated with a pro-fibrotic phenotype. Our results indicate that adipocyte hypertrophy induced by INSTIs is involved via hypoxia (revealed by a greater hypoxia-inducible-factor-1-alpha gene expression) in fat fibrosis, beiging inhibition, and thus (via positive feedback), probably, further hypertrophy and associated insulin resistance.

Adipose tissue, systematic inflammation, and neurodegenerative diseases.

Obesity is associated with several diseases, including mental health. Adipose tissue is distributed around the internal organs, acting in the regulation of metabolism by storing and releasing fatty acids and adipokine in the tissues. Excessive nutritional intake results in hypertrophy and proliferation of adipocytes, leading to local hypoxia in adipose tissue and changes in these adipokine releases. This leads to the recruitment of immune cells to adipose tissue and the release of pro-inflammatory cytokines. The presence of high levels of free fatty acids and inflammatory molecules interfere with intracellular insulin signaling, which can generate a neuroinflammatory process. In this review, we provide an up-to-date discussion of how excessive obesity can lead to possible cognitive dysfunction. We also address the idea that obesity-associated systemic inflammation leads to neuroinflammation in the brain, particularly the hypothalamus and hippocampus, and that this is partially responsible for these negative cognitive outcomes. In addition, we discuss some clinical models and animal studies for obesity and clarify the mechanism of action of anti-obesity drugs in the central nervous system.

Genetic variants of the hypoxia-inducible factor 3 alpha subunit (Hif3a) gene in the Fat and Lean mouse selection lines.

Adipose tissue hypoxia and members of the hypoxia-inducible factor alpha (HIFA) are involved in development of obesity. However, the mechanism and functions of HIF3A, one of three HIFA paralogs, in fat deposition have not been sufficiently studied. In the present study, we investigated whether Hif3a sequence variants are associated with divergent fat deposition in mouse selection lines for fatness and leanness. Sequencing and RFLP were used to analyse sequence variants within Hif3a. To identify candidate regulatory variants, we performed literature screening and used databases and bioinformatics tools like Ensembl, MethPrimer, TargetScanMouse, miRDB, PolyAsite, RISE, LncRRIsearch, RNAfold, PredictProtein, CAIcal, and switches.ELM Resource. There are 90 sequence variants in Hif3a between the two mouse lines. While most Fat line variants locate within intronic regions, Lean line variants are mainly in 3' UTR. We constructed a map of Hif3a potential regulatory regions and identified 39 regulatory variants by integrating data on constrained and regulatory elements, CpGs, and miRNAs and lncRNAs binding sites. Moreover, 3' UTR and two exonic variants may influence mRNA stability, translation rate and protein functionality. We propose as priority candidates for further functional studies a missense (rs37398126) and synonymous (rs37739792) variants, and intronic (rs47471302) variant that overlap conserved element in promoter region and predicted lncRNAs binding site. The results indicate a potential involvement of Hif3a in fat deposition. Additionally, approach used in the present study may serve as a general guideline for constructing an integrative gene map for prioritizing candidate gene variants with phenotypic effects.

Astaxanthin, a Marine Carotenoid, Maintains the Tolerance and Integrity of Adipose Tissue and Contributes to Its Healthy Functions.

Recently, obesity-induced insulin resistance, type 2 diabetes, and cardiovascular disease have become major social problems. We have previously shown that Astaxanthin (AX), which is a natural antioxidant, significantly ameliorates obesity-induced glucose intolerance and insulin resistance. It is well known that AX is a strong lipophilic antioxidant and has been shown to be beneficial for acute inflammation. However, the actual effects of AX on chronic inflammation in adipose tissue (AT) remain unclear. To observe the effects of AX on AT functions in obese mice, we fed six-week-old male C57BL/6J on high-fat-diet (HFD) supplemented with or without 0.02% of AX for 24 weeks. We determined the effect of AX at 10 and 24 weeks of HFD with or without AX on various parameters including insulin sensitivity, glucose tolerance, inflammation, and mitochondrial function in AT. We found that AX significantly reduced oxidative stress and macrophage infiltration into AT, as well as maintaining healthy AT function. Furthermore, AX prevented pathological AT remodeling probably caused by hypoxia in AT. Collectively, AX treatment exerted anti-inflammatory effects via its antioxidant activity in AT, maintained the vascular structure of AT and preserved the stem cells and progenitor’s niche, and enhanced anti-inflammatory hypoxia induction factor-2α-dominant hypoxic response. Through these mechanisms of action, it prevented the pathological remodeling of AT and maintained its integrity.

Abstract 10267: Thermogenic Modulation of Perivascular Adipose Tissue Ameliorates Cardioautonomic Deterioration in Prediabetes

Introduction: Cardiac autonomic neuropathy, a risk factor of cardiovascular mortality, is a common manifestation of prediabetes. Evidence points to perivascular adipose tissue inflammation as a quintessential instigator of cardiovascular dysfunction in metabolic impairment. Interventions tailored to ameliorate such subtle cardiovascular involvement have not been forthcoming. Data emerging from our laboratory implicate alteration of adipocyte mitochondrial bioenergetics, particularly an upregulation of uncoupling protein 1 (UCP1) expression and subsequent augmentation of adipose tissue hypoxia, as a potential culprit driving localized adipose inflammation. Hypothesis: Inhibition of UCP1-mediated thermogenesis or activation of the alternative thermogenic pathway, futile creatine cycling, through supplementation with phosphate or creatine monohydrate, respectively, may ameliorate the inflammatory phenotype observed in non-obese prediabetic rats. Methods: A non-obese prediabetic rat model, developed in our laboratory was used. This phenotype is evoked by 12 weeks of hypercaloric feeding causing localized perivascular inflammation in absence of systemic markers of inflammation. Cardioautonomic function was assessed by invasive hemodynamics. Localized adipose tissue inflammation and macrophage polarization were examined. Results: UCP1 inhibition by phosphate supplementation reversed the blunted parasympathetic baroreflex sensitivity observed in prediabetic rats. This was associated with the alleviation of perivascular adipose tissue hypoxia, inflammation, and altered macrophage polarization. These changes were accompanied by normalization of metabolic efficiency that increased in prediabetic rats due to UCP1 upregulation. Similar functional effects were observed after creatine supplementation without changes in metabolic efficiency. Conclusions: Bypassing UCP1-mediated thermogenesis upregulated by increased caloric intake alleviates cardioautonomic deterioration triggered by perivascular inflammation. This is achieved by UCP1 inhibition with a potential risk of increased metabolic efficiency and weight gain, or by activation of the alternative thermogenic pathway of creatine cycling.