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Model of how hypoxia may lead to the recruitment of brite adipocytes and the “browning” of white adipose tissue depots through stimulating the production and release of lactate. FA, fatty acid; UCP1, uncoupling protein-1.
Source publication
Relative hypoxia has been shown to develop in white adipose tissue depots of different types of obese mouse (genetic, dietary), and this leads to substantial changes in white adipocyte function. These changes include increased production of inflammation-related adipokines (such as IL-6, leptin, Angptl4, and VEGF), an increase in glucose utilization...
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Background
Recruitment and activation of brown adipose tissue (BAT) results in increased energy expenditure (EE) via thermogenesis and represents an intriguing therapeutic approach to combat obesity and treat associated diseases. Thermogenesis requires an increased and efficient supply of energy substrates and oxygen to the BAT. The hemoprotein my...
An emerging strategy for reducing obesity is induction of brown fat type phenotype in white adipose tissue. Chlorogenic acid (CGA), a dietary polyphenol, has been reported to modulate lipid and glucose metabolism, and improve glucose tolerance. However, information on its role in adipocyte browning is lacking. The effect of CGA on browning of 3T3-L...
Objective: Peroxisome proliferator-activated receptors (PPARs) are key transcription factors that regulate adipose development and function, and the conversion of white into brown-like adipocytes. Here we investigated whether PPARα and PPARγ activation synergize to induce browning of white fat.
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Obesity, an excess accumulation of white adipose tissue (WAT), has become a global epidemic and is associated with complex diseases, such as type 2 diabetes and cardiovascular diseases. Presently, there are no safe and effective therapeutic agents to treat obesity. In contrast to white adipocytes that store energy as triglycerides in unilocular lip...
Citations
... Large amounts of proinflammatory cytokines, such as interferon-γ, are released by activated immune cells during obesity, enhancing the proinflammatory microenvironment of adipose tissue (55). In addition, local adipocyte enlargement causes hypoxia and induces mature adipocytes to secrete pro-inflammatory mediators including cytokines and chemokines such as CCL5, PAI-1, IL-6, and microRNAs (56)(57)(58)(59). ...
Background
Global health issues related to obesity are growing. Visceral adipose tissue (VAT) significantly contributes to complications associated with obesity. Reducing adipose tissue accumulation can improves inflammation. However, it is still unknown how the systemic immune-inflammation index (SII) and VAT area are related.
Methods
With the help of multivariate linear regression and smooth curve fitting, the relationship between SII and VAT area was explored with data from the 2013 and 2014 National Health and Nutrition Examination Survey (NHANES). Analyzing subgroups and testing for interaction were used to investigate whether the relationship was accurate across demographics.
Results
From 20 to 59 years of age, 3,290 individuals were observed to have a positive correlation between SII and VAT area. In accordance with the fully adjusted model, the VAT area increased by 9.34 cm ² for every unit increase in log SII [ β = 9.34, 95% CI (4.02, 14.67)]. In the highest quartile of SII, the VAT area was 5.46 cm ² [ β = 5.46, 95% CI (2.21, 8.71)] higher than that in the lowest quartile. Additionally, the population that was overweight or obese showed a stronger positive correlation.
Conclusion
SII has a positive correlation with VAT area in US adults. SII may be valuable in clinical applications to evaluate the severity of VAT area.
... However, little consideration has been given to how the surge in oxygen consumption upon activation is virtually creating hypoxia. Likewise, in obesity, brown adipocytes experience increased lipid deposition, leading to the enlargement of BAT and vascular rarefaction [1,6,7]. Hypoxic conditions within adipose tissue are also associated with insulin resistance and obesity-related complications, as they promote inflammation and impair adipokine secretion. ...
MicroRNAs (miRNAs) are short sequences of single-stranded non-coding RNAs that target messenger RNAs, leading to their repression or decay. Interestingly, miRNAs play a role in the cellular response to low oxygen levels, known as hypoxia, which is associated with reactive oxygen species and oxidative stress. However, the physiological implications of hypoxia-induced miRNAs (“hypoxamiRs”) remain largely unclear. Here, we investigate the role of miR-210 in brown adipocyte differentiation and thermogenesis. We treated the cells under sympathetic stimulation with hypoxia, CoCl2, or IOX2. To manipulate miR-210, we performed reverse transfection with antagomiRs. Adipocyte markers expression, lipid accumulation, lipolysis, and oxygen consumption were measured. Hypoxia hindered BAT differentiation and suppressed sympathetic stimulation. Hypoxia-induced HIF-1α stabilization increased miR-210 in brown adipocytes. Interestingly, miR-210-5p enhanced differentiation under normoxic conditions but was insufficient to rescue the inhibition of brown adipocyte differentiation under hypoxic conditions. Although adrenergic stimulation activated HIF-1α signaling and upregulated miR-210 expression, inhibition of miR-210-5p did not significantly influence UCP1 expression or oxygen consumption. In summary, hypoxia and adrenergic stimulation upregulated miR-210, which impacted brown adipocyte differentiation and thermogenesis. These findings offer new insights for the physiological role of hypoxamiRs in brown adipose tissue, which could aid in understanding oxidative stress and treatment of metabolic disorders.
... Obesity can cause a rapid increase in adipose tissue (AT). The rate of angiogenesis may not keep up with AT expansion, leading to local hypoxia and fibrosis in AT (13,20,33). These changes promote the release of inflammatory factors and enhance the local inflammatory response, ultimately leading to fat cell dysfunction, metabolic alterations, and reduced immunity (9,20,24). ...
Background
Observational studies have indicated that obesity is a risk factor for anorectal abscess (ARB). However, it remains unclear whether a causal genetic relationship exists between obesity and ARB.
Methods
Univariate and multivariate Mendelian randomization (MR) were conducted using data from a large, published genome-wide association study (GWAS) of European ancestry to infer a causal relationship between obesity and ARB. Inverse variance weighted (IVW) analysis served as the primary analysis method, with results reported as odds ratios (OR).
Results
MR analysis revealed that body mass index (BMI) positively affects ARB (OR 1.974, 95% confidence interval (CI) 1.548–2.519, p = 4.34 × 10⁻⁸). The weighted median method (OR = 1.879, 95% CI 1.248–2.829, p = 0.002) and Bayesian model averaging (BMA) (OR = 1.88, 95% CI 1.477–2.392, p = 2.85 × 10⁻⁷) also demonstrated consistent results. Subsequently, the impact of several obesity-related characteristics on ARB was assessed. Body fat percentage (BF), whole body fat mass (FM), waist circumference (WC), and hip circumference (HC) were found to be causally associated with an increased risk of ARB. However, these associations vanished after adjusting for BMI effects.
Conclusion
The study confirms a positive causal effect of obesity on ARB, highlighting that reasonable weight control is an important strategy to reduce the incidence of ARB.
... Hypoxia is often perceived as a pathological state or a symptom of disease [23,24]; however, it can also serve as a therapeutic tool in the treatment of obesity and its coexisting conditions, such as cardiovascular, respiratory, and nervous system diseases [25]. Compensatory positive mechanisms and the body's responses to hypoxia have been presented, involving the respiratory system (improved respiratory function and increased diffusion in lungs), the cardiovascular system (elevated heart rate, peripheral vasodilation, and blood pressure normalization), cellular and metabolic processes (angiogenesis, increased insulin sensitivity, enzymatic activation, and mitochondrial biogenesis), as well as body mass regulation (leptin modulation, activation of the adrenergic system, appetite suppression, and serotonin production) [25,26]. ...
Background: Obesity, a common lifestyle-related condition, is correlated with factors like inadequate physical activity. Its connection to diverse health issues presents a significant challenge to healthcare. This pilot study investigated the effects of hypoxic training on aerobic capacity and biometric-structural indicators in obese women. The secondary objective was to determine the feasibility, effectiveness, and safety of the planned research procedures and their potential for larger-scale implementation. Material and methods: Forty-one non-trained women with first-degree obesity were randomly assigned to even normobaric hypoxic training (H + E), normoxic training (E), passive exposure to hypoxia (H), and a control group (C). Training sessions were conducted three times a week for four weeks (12 training sessions). Body composition parameters were assessed, metabolic thresholds were determined, and maximal oxygen consumption (VO2max) was measured before and after interventions. Results: The results demonstrated that training in hypoxic conditions significantly affected somatic parameters, with the H + E group achieving the best outcomes in terms of weight reduction and improvements in body composition indicators (p < 0.001). Normoxic training also induced a positive impact on body weight and body composition, although the results were less significant compared to the H + E group (p < 0.001). Additionally, training in hypoxic conditions significantly improved the aerobic capacity among the participants (p < 0.001). The H + E group achieved the best results in enhancing respiratory endurance and oxygen consumption (p < 0.001). Conclusions: The results of this pilot study suggest, that hypoxic training can be effective for weight reduction and improving the aerobic capacity in obese women. Despite study limitations, these findings indicate that hypoxic training could be an innovative approach to address obesity and related conditions. Caution is advised in interpreting the results, considering both the strengths and limitations of the pilot study. Before proceeding to a larger-scale study, the main study should be expanded, including aspects such as dietary control, monitoring physical activity, and biochemical blood analysis.
... In humans, the increase is about 2-3 [55]. This new anatomy implies an increased distance from capillaries and consequent hypoxia, as demonstrated by HIFα production [56]. Furthermore, it is well known that an excess of nutrients can cause, per se, endoplasmic reticulum stress in adipocytes [57]. ...
... increased distance from capillaries and consequent hypoxia, as demonstrated by HIFα production [56]. Furthermore, it is well known that an excess of nutrients can cause, per se, endoplasmic reticulum stress in adipocytes [57]. ...
White and brown adipose tissues are organized to form a real organ, the adipose organ, in mice and humans. White adipocytes of obese animals and humans are hypertrophic. This condition is accompanied by a series of organelle alterations and stress of the endoplasmic reticulum. This stress is mainly due to reactive oxygen species activity and accumulation, lending to NLRP3 inflammasome activation. This last causes death of adipocytes by pyroptosis and the formation of large cellular debris that must be removed by macrophages. During their chronic scavenging activity, macrophages produce several secretory products that have collateral consequences, including interference with insulin receptor activity, causing insulin resistance. The latter is accompanied by an increased noradrenergic inhibitory innervation of Langerhans islets with de-differentiation of beta cells and type 2 diabetes. The whitening of brown adipocytes could explain the different critical death size of visceral adipocytes and offer an explanation for the worse clinical consequence of visceral fat accumulation. White to brown transdifferentiation has been proven in mice and humans. Considering the energy-dispersing activity of brown adipose tissue, transdifferentiation opens new therapeutic perspectives for obesity and related disorders.
... BAT is among the most vascularized tissues in the body, averaging ~1.2 capillaries per BA (versus only ~0.4 capillaries per white adipocyte) [87][88][89][90][91]. A substantial blood supply is required to provide glucose, fatty acids, nutrients, and oxygen to fuel thermogenesis and rapidly distribute heat throughout the body [98]. Vascular cells also produce soluble and insoluble factors critical for BA functions and homeostasis; conversely, BAs produce a range of growth factors and cytokines that collectively modulate vascular growth, survival, remodeling, regression, and blood perfusion [89,91,99]. ...
Transplanting cell cultured brown adipocytes (BAs) represents a promising approach to prevent and treat obesity (OB) and its associated metabolic disorders, including type 2 diabetes mellitus (T2DM). However, transplanted BAs have a very low survival rate in vivo. The enzymatic dissociation during the harvest of fully differentiated BAs also loses significant cells. There is a critical need for novel methods that can avoid cell death during cell preparation, transplantation, and in vivo. Here, we reported that preparing BAs as injectable microtissues could overcome the problem. We found that 3D culture promoted BA differentiation and UCP-1 expression, and the optimal initial cell aggregate size was 100 μm. The microtissues could be produced at large scales via 3D suspension assisted with a PEG hydrogel and could be cryopreserved. Fabricated microtissues could survive in vivo for long term. They alleviated body weight and fat gain and improved glucose tolerance and insulin sensitivity in high-fat diet (HFD)-induced OB and T2DM mice. Transplanted microtissues impacted multiple organs, secreted protein factors, and influenced the secretion of endogenous adipokines. To our best knowledge, this is the first report on fabricating human BA microtissues and showing their safety and efficacy in T2DM mice. The proposal of transplanting fabricated BA microtissues, the microtissue fabrication method, and the demonstration of efficacy in T2DM mice are all new. Our results show that engineered 3D human BA microtissues have considerable advantages in product scalability, storage, purity, safety, dosage, survival, and efficacy.
... WR can increase adipocyte oxygen consumption and hypoxic conditions, increase HIF-1-related gene expression and lactic acid accumulation, and stimulate the mobilization of adipose tissue from the liver. HIF-1α overexpression causes insulin resistance and adipose tissue inflammation in mouse adipocytes [109]. During the WR phase of WC, the expression of oxidative stress-related genes increased in the subcutaneous adipose tissue of the subjects. ...
As a result of the obesity epidemic, more people are concerned about losing weight; however, weight regain is common, leading to repeated weight loss and weight cycling. The health benefits of early weight loss are nullified by weight regain after weight cycling, which has much more severe metabolic consequences. Weight cycling alters body composition, resulting in faster fat recovery and slower muscle reconstruction. This evident fat accumulation, muscle loss, and ectopic fat deposition destroy the intestinal barrier, increase the permeability of the small intestinal epithelium, and cause the lipotoxicity of lipid metabolites and toxins to leak into extraintestinal tissues and circulation. It causes oxidative stress and hypoxia in local tissues and immune cell infiltration in various tissues, all contributing to the adaptation to this metabolic change. Immune cells transmit inflammatory responses in adipose and skeletal muscle tissue by secreting cytokines and adipokines, which mediate immune cell pathways and cause metaflammation and inefficient metabolic degradation. In this review, we focus on the regulatory function of the immunological microenvironment in the final metabolic outcome, with a particular emphasis on the cellular and molecular processes of local and systemic metaflammation induced by weight cycling-induced changes in body composition. Metaflammation in adipose and muscle tissues that is difficult to relieve may cause weight cycling. As this chronic low-grade inflammation spreads throughout the body, metabolic complications associated with weight cycling are triggered. Inhibiting the onset and progression of metabolic inflammation and enhancing the immune microenvironment of adipose and muscle tissues may be the first step in addressing weight cycling.
... The exaggerated pulmonary inflammation triggered by influenza viruses can induce the acute lung injury leading to development of hypoxia [36]. Moreover, hypoxia can develop in rapidly growing white adipose tissue and tumours [37,38]. While the alveolar macrophages reside in the lungs, the peritoneal macrophages reside in the adipose tissue and in the tumours. ...
Macrophages are the most abundant cells in infected tissue and are involved in the clearing infection, and immunomodulation of the innate and adaptive immune response. NS80 virus of influenza A virus, which encodes only the first 80 aa of the NS1 protein, suppresses the immune host response and is associated with enhanced pathogenicity. Hypoxia promotes infiltration of peritoneal macrophages into the adipose tissue and production of cytokines. To understand the role of hypoxia in the regulation of immune response, macrophages were infected with A/WSN/33 (WSN) and NS80 virus, and transcriptional profiles of the RIG-I-like receptor signalling pathway and expression of cytokines were evaluated in normoxia and hypoxia. Hypoxia inhibited the proliferation of IC-21 cells, downregulated the RIG-I-like receptor signalling pathway, and inhibited transcriptional activity of IFN-α, IFN-β, IFN-ε, and IFN-λ mRNA in infected macrophages. While transcription of IL-1β and Casp-1 mRNAs were increased in infected macrophages in normoxia, hypoxia resulted in decreased transcription activity of IL-1β and Casp-1 mRNAs. Hypoxia significantly affected expression of the translation factors IRF4, IFN-γ, and CXCL10 involved in regulation of immune response and polarization of the macrophages. The expression of pro-inflammatory cytokines such as sICAM-1, IL-1α, TNF-α, CCL2, CCL3, CXCL12, and M-CSF was to a large extent affected in uninfected and infected macrophages cultivated in hypoxia. The NS80 virus increased the expression of M-CSF, IL-16, CCL2, CCL3, and CXCL12, especially under hypoxia. The results show that hypoxia may play an important role in peritoneal macrophage activation, regulates the innate and adaptive immune response, changes production of pro-inflammatory cytokines, promotes macrophage polarization, and could affect the function of other immune cells.
... One major mediator of this response is hypoxia-inducible factor 1α [55]. Pro-inflammatory mediators secreted by mature adipocytes during hypoxia include chemokines and cytokines such as PAI-1, CCL5, and IL-6 as well as micro RNAs [65][66][67][68] (Fig. 3). A subset of macrophages is closely associated with the vasculature and characterized by the expression of lymphatic vessel endothelial hyaluronan receptor 1. ...
Obesity usually is accompanied by inflammation of fat tissue, with a prominent role of visceral fat. Chronic inflammation in obese fat tissue is of a lower grade than acute immune activation for clearing the tissue from an infectious agent. It is the loss of adipocyte metabolic homeostasis that causes activation of resident immune cells for supporting tissue functions and regaining homeostasis. Initially, the excess influx of lipids and glucose in the context of overnutrition is met by adipocyte growth and proliferation. Eventual lipid overload of hypertrophic adipocytes leads to endoplasmic reticulum stress and the secretion of a variety of signals causing increased sympathetic tone, lipolysis by adipocytes, lipid uptake by macrophages, matrix remodeling, angiogenesis, and immune cell activation. Pro-inflammatory signaling of adipocytes causes the resident immune system to release increased amounts of pro-inflammatory and other mediators resulting in enhanced tissue-protective responses. With chronic overnutrition, these protective actions are insufficient, and death of adipocytes as well as senescence of several tissue cell types is seen. This structural damage causes the expression or release of immunostimulatory cell components resulting in influx and activation of monocytes and many other immune cell types, with a contribution of stromal cells. Matrix remodeling and angiogenesis is further intensified as well as possibly detrimental fibrosis. The accumulation of senescent cells also may be detrimental via eventual spread of senescence state from affected to neighboring cells by the release of microRNA-containing vesicles. Obese visceral fat inflammation can be viewed as an initially protective response in order to cope with excess ambient nutrients and restore tissue homeostasis but may contribute to tissue damage at a later stage.
... Local tissue hypoxia has been hypothesized as a contributing factor to the development of visceral white adipose tissue (vWAT) inflammation and whole-body insulin resistance in obese people [13][14][15][16]. However, this assumption has been challenged [17][18][19], such that it remains unclear whether hypoxia is a cause or a consequence of obesity-associated metabolic disorders. Obesity is accompanied by adipocyte enlargement that increases inter-capillary distance, thereby markedly decreasing blood perfusion to each adipocyte and inducing an overall decline in adipose tissue oxygen tension. ...
... Despite these phenotypically "brown" features, the levels of P2RX5, a marker of classical brown adipose tissue, were reduced ( Figure 3F). [17][18][19][20]. Data presented as means ± SEM. ...
Obstructive sleep apnea (OSA) is a highly prevalent condition, characterized by intermittent hypoxia (IH), sleep disruption, and altered autonomic nervous system function. OSA has been independently associated with dyslipidemia, insulin resistance, and metabolic syndrome. Brown adipose tissue (BAT) has been suggested as a modulator of systemic glucose tolerance through adaptive thermogenesis. Reductions in BAT mass have been associated with obesity and metabolic syndrome. No studies have systematically characterized the effects of chronic IH on BAT. Thus, we aimed to delineate IH effects on BAT and concomitant metabolic changes. C57BL/6J 8-week-old male mice were randomly assigned to IH during sleep (alternating 90 s cycles of 6.5% FIO2 followed by 21% FIO2) or normoxia (room air, RA) for 10 weeks. Mice were subjected to glucose tolerance testing and 18F-FDG PET–MRI towards the end of the exposures followed by BAT tissues analyses for morphological and global transcriptomic changes. Animals exposed to IH were glucose intolerant despite lower total body weight and adiposity. BAT tissues in IH-exposed mice demonstrated characteristic changes associated with “browning”—smaller lipids, increased vascularity, and a trend towards higher protein levels of UCP1. Conversely, mitochondrial DNA content and protein levels of respiratory chain complex III were reduced. Pro-inflammatory macrophages were more abundant in IH-exposed BAT. Transcriptomic analysis revealed increases in fatty acid oxidation and oxidative stress pathways in IH-exposed BAT, along with a reduction in pathways related to myogenesis, hypoxia, and IL-4 anti-inflammatory response. Functionally, IH-exposed BAT demonstrated reduced absorption of glucose on PET scans and reduced phosphorylation of AKT in response to insulin. Current studies provide initial evidence for the presence of a maladaptive response of interscapular BAT in response to chronic IH mimicking OSA, resulting in a paradoxical divergence, namely, BAT browning but tissue-specific and systemic insulin resistance. We postulate that oxidative stress, mitochondrial dysfunction, and inflammation may underlie these dichotomous outcomes in BAT.
