Adipose tissue fibrosis is a hallmark of malfunction that is linked to insulin resistance and type 2 diabetes; however, what regulates this process remains unclear. Here we show that the PRDM16 ...transcriptional complex, a dominant activator of brown/beige adipocyte development, potently represses adipose tissue fibrosis in an uncoupling protein 1 (UCP1)-independent manner. By purifying the PRDM16 complex, we identified GTF2IRD1, a member of the TFII-I family of DNA-binding proteins, as a cold-inducible transcription factor that mediates the repressive action of the PRDM16 complex on fibrosis. Adipocyte-selective expression of GTF2IRD1 represses adipose tissue fibrosis and improves systemic glucose homeostasis independent of body-weight loss, while deleting GTF2IRD1 promotes fibrosis in a cell-autonomous manner. GTF2IRD1 represses the transcription of transforming growth factor β-dependent pro-fibrosis genes by recruiting PRDM16 and EHMT1 onto their promoter/enhancer regions. These results suggest a mechanism by which repression of obesity-associated adipose tissue fibrosis through the PRDM16 complex leads to an improvement in systemic glucose homeostasis.
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•GTF2IRD1 is a transcription factor that forms a complex with PRDM16 and EHMT1•A PRDM16-GTF2IRD1 complex cell-autonomously represses adipose tissue fibrosis•Repression of adipose tissue fibrosis improves systemic glucose homeostasis•GTF2IRD1 expression inversely correlates with subcutaneous WAT fibrosis in humans
Hasegawa et al. identify GTF2IRD1 as a cold-inducible transcription factor that represses adipose tissue fibrosis through a PRDM16-EHMT1 complex. Repression of adipose tissue fibrosis by the complex improves systemic glucose homeostasis independent of UCP1-mediated thermogenesis and body weight. In humans, GTF2IRD1 expression inversely correlates with subcutaneous WAT fibrosis and visceral adiposity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Adipose tissues dynamically remodel their cellular composition in response to external cues by stimulating beige adipocyte biogenesis; however, the developmental origin and pathways regulating this ...process remain insufficiently understood owing to adipose tissue heterogeneity. Here, we employed single-cell RNA-seq and identified a unique subset of adipocyte progenitor cells (APCs) that possessed the cell-intrinsic plasticity to give rise to beige fat. This beige APC population is proliferative and marked by cell-surface proteins, including PDGFRα, Sca1, and CD81. Notably, CD81 is not only a beige APC marker but also required for de novo beige fat biogenesis following cold exposure. CD81 forms a complex with αV/β1 and αV/β5 integrins and mediates the activation of integrin-FAK signaling in response to irisin. Importantly, CD81 loss causes diet-induced obesity, insulin resistance, and adipose tissue inflammation. These results suggest that CD81 functions as a key sensor of external inputs and controls beige APC proliferation and whole-body energy homeostasis.
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•Beige fat progenitors are marked by cell surface proteins, PDGFRα, Sca1, and CD81•Beige APC proliferation is regulated by temperature, genetic background, and aging•CD81 mediates integrin-FAK signaling in response to irisin•CD81 loss causes obesity, insulin resistance, and adipose tissue inflammation
A subset of adipocyte progenitor cells give rise to beige fat through signaling responses to irisin through the action of specific integrins and the co-receptor CD81.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
The main goal of a health system is to maintain or improve people’s health. The COVID-19 pandemic showed the fragility of health systems worldwide. In Mexico, the pandemic affected the ...performance of the health system, along with the presence of contextual conditions such as its segmentation and high prevalence of chronic diseases.
Aims
To analyze from an approach to the functions of the health system, the service delivery, human resources, financing, and stewardship/governance in the local health services of five states of Mexico, from the perspective of the staff working in health centers.
Methods
This is an exploratory qualitative study conducted from November 2020 to August 2021, involving 124 health professionals from 39 health facilities (18 rural and 21 urban). The technique used was the semi-structured interview. Interview guides were developed according to core topics. Subsequently, the thematic analysis method was used.
Results
The lack of financial resources delayed prevention efforts and made it difficult for health centers to adapt to the crisis. Inequity was found in the distributive efficiency of staff between rural and urban areas and levels of care. In addition, there was evidence of capacity for coordination, capacity sharing, and joint participation between health institutions, civil authorities, and the population to face the emergency.
Conclusions
We identified relevant public health actions that showed the capacity of local health services to organize a response to the pandemic at the level of the actors responsible for these services.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK, VSZLJ
Abstract
The concept of resilience was applied to the public health field to investigate the way health systems are impacted by health crises, what conditions allow them to mitigate the blow and how ...they reorganize once the crisis is over. In 2020, the COVID-19 pandemic caused by the SARS-CoV-2 virus represented a global challenge demanding immediate response to an unprecedented health crisis. Various voices drew attention to the intensity of the crisis in countries with greater inequalities, where the pandemic converged with other social emergencies. We documented the experiences of health personnel who faced the pandemic at the primary care level while simultaneously maintaining the functioning of other areas of medical care. Our results derived from a qualitative study comprising 103 participants from five states of Mexico. We aimed to show through inferential analysis their perspective on what we call ‘the resilience of local health systems’. We observed three stages of experience during the crisis: (a) Preparation (official guidelines received to organize care, training and planning of epidemiological surveillance); (b) Adaptation (performance of community-based prevention activities, infrastructure modifications, telehealth); and (c) Learning (participatory governance with city councils, business sector and organized population). The study suggests that the local health systems analysed benefited from the initiatives of health personnel that in some cases positively exceeded their duties. In terms of the resilience analysis, they were able to handle the impact of the crisis and cope with it. Their transformative capacity came from the strategies implemented to adapt health services by managing institutional resources. Their experience represents a lesson on the strengthening of the essential functions of health systems and shows a way to address successfully the increasingly complex health challenges of the present and future times.
Bariatric surgery results in reduced muscle mass as weight is lost, but postoperative changes in muscle strength and performance are incompletely understood.
To examine changes in body composition, ...strength, physical activity, and physical performance following Roux-en-Y gastric bypass (RYGB).
In a prospective cohort of 47 adults (37 women, 10 men) aged 45 ± 12 years (mean ± SD) with body mass index (BMI) 44 ± 8 kg/m2, we measured body composition by dual-energy X-ray absorptiometry, handgrip strength, physical activity, and physical performance (chair stand time, gait speed, 400-m walk time) before and 6 and 12 months after RYGB. Relative strength was calculated as absolute handgrip strength/BMI and as absolute strength/appendicular lean mass (ALM).
Participants experienced substantial 12-month decreases in weight (-37 ± 10 kg or 30% ± 7%), fat mass (-48% ± 12%), and total lean mass (-13% ± 6%). Mean absolute strength declined by 9% ± 17% (P < 0.01). In contrast, relative strength increased by 32% ± 25% (strength/BMI) and 9% ± 20% (strength/ALM) (P < 0.01 for both). There were clinically significant postoperative improvements in all physical performance measures, including mean improvement in gait speed of >0.1 m/s (P < 0.01) and decrease in 400-m walk time of nearly a full minute.
In the setting of dramatic weight loss, lean mass and absolute grip strength declined after RYGB. However, relative muscle strength and physical function improved meaningfully and are thus noteworthy positive outcomes of gastric bypass.
East Asians (EAs) experience worse metabolic health outcomes compared to other ethnic groups at lower body mass indices; however, the potential role of the gut microbiota in contributing to these ...health disparities remains unknown. We conducted a multi-omic study of 46 lean and obese East Asian and White participants living in the San Francisco Bay Area, revealing marked differences between ethnic groups in bacterial richness and community structure. White individuals were enriched for the mucin-degrading
. East Asian subjects had increased levels of multiple bacterial phyla, fermentative pathways detected by metagenomics, and the short-chain fatty acid end-products acetate, propionate, and isobutyrate. Differences in the gut microbiota between the East Asian and White subjects could not be explained by dietary intake, were more pronounced in lean individuals, and were associated with current geographical location. Microbiome transplantations into germ-free mice demonstrated stable diet- and host genotype-independent differences between the gut microbiotas of East Asian and White individuals that differentially impact host body composition. Taken together, our findings add to the growing body of literature describing microbiome variations between ethnicities and provide a starting point for defining the mechanisms through which the microbiome may shape disparate health outcomes in East Asians.
Integrins are cell adhesion receptors that dimerize to mediate cell–cell interactions and regulate processes, including proliferation, inflammation, and tissue repair. The role of integrins in ...regulating insulin signaling is incompletely understood. We have previously shown that binding of the integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) to the αvβ5 integrin promotes termination of insulin receptor signaling in mice. Upon ligation of MFGE8, integrin β5 complexes with the insulin receptor beta (IRβ) in skeletal muscle, resulting in dephosphorylation of IRβ and reduction of insulin-stimulated glucose uptake. Here, we investigate the mechanism by which the interaction between β5 and IRβ impacts IRβ phosphorylation status. We show in in vitro and in vivo in skeletal muscle in mice that antibody-mediated blockade of the β5 integrin inhibits and recombinant MFGE8 promotes PTP1B binding to and dephosphorylation of IRβ resulting in increased or reduced insulin-stimulated glucose uptake, respectively. The β5–PTP1B complex is recruited by MFGE8 to IRβ leading to termination of canonical insulin signaling. β5 blockade enhances insulin-stimulated glucose uptake in wildtype but not Ptp1b KO mice indicating that PTP1B functions downstream of MFGE8 in modulating insulin receptor signaling. Furthermore, in a human cohort, we report serum MFGE8 levels correlate with indices of insulin resistance. These data provide mechanistic insights into the role of MFGE8 and β5 in regulating insulin signaling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Type 2 diabetes presents at a lower body mass index (BMI) in Chinese individuals than in white individuals. We sought to determine the role of subcutaneous adipose tissue (SCAT)-intrinsic factors, vs ...BMI or adiposity per se, in the vulnerability of Chinese individuals to obesity-associated impairment of insulin sensitivity.
Thirty-two Chinese and 30 white men and women from a cohort in the San Francisco Bay Area underwent anthropometric measurements, body composition (dual-energy X-ray absorptiometry) analyses, and measurement of fasting plasma glucose and insulin. Forty-eight also provided abdominal SCAT samples for transcriptional and biochemical analyses of tissue fibrosis.
BMI correlated with total body fat in white (r = 0.74, P < 0.001) but not Chinese individuals, whereas BMI correlated with visceral adipose tissue (VAT) accrual in both ethnicities (r = 0.88 and 0.81, respectively; P < 0.01). Insulin resistance (homeostatic model assessment of insulin resistance) worsened with VAT mass, but not total body fat, in Chinese subjects (r = 0.63, P < 0.01), whereas it worsened with both in white individuals. By contrast, SCAT mRNA levels of genes encoding profibrotic proteins rose remarkably along with both BMI and VAT mass in Chinese but not white subjects. Similarly, SCAT levels of hydroxyproline, an indicator of tissue collagen content that correlated with increasing VAT mass, were higher in Chinese vs white subjects, particularly in the setting of relative insulin resistance.
Our findings dissociate BMI from adiposity in Chinese individuals and instead highlight SCAT fibrosis as a process linked to visceral adiposity and insulin resistance in this group.
Plant-derived lignans, consumed daily by most individuals, are thought to protect against cancer and other diseases
; however, their bioactivity requires gut bacterial conversion to enterolignans
. ...Here, we dissect a four-species bacterial consortium sufficient for all five reactions in this pathway. A single enzyme (benzyl ether reductase, encoded by the gene ber) was sufficient for the first two biotransformations, variable between strains of Eggerthella lenta, critical for enterolignan production in gnotobiotic mice and unique to Coriobacteriia. Transcriptional profiling (RNA sequencing) independently identified ber and genomic loci upregulated by each of the remaining substrates. Despite their low abundance in gut microbiomes and restricted phylogenetic range, all of the identified genes were detectable in the distal gut microbiomes of most individuals living in northern California. Together, these results emphasize the importance of considering strain-level variations and bacterial co-occurrence to gain a mechanistic understanding of the bioactivation of plant secondary metabolites by the human gut microbiome.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Impaired white adipose tissue (WAT) function has been recognized as a critical early event in obesity‐driven disorders, but high buoyancy, fragility, and heterogeneity of primary adipocytes have ...largely prevented their use in drug discovery efforts highlighting the need for human stem cell‐based approaches. Here, human stem cells are utilized to derive metabolically functional 3D adipose tissue (iADIPO) in a microphysiological system (MPS). Surprisingly, previously reported WAT differentiation approaches create insulin resistant WAT ill‐suited for type‐2 diabetes mellitus drug discovery. Using three independent insulin sensitivity assays, i.e., glucose and fatty acid uptake and suppression of lipolysis, as the functional readouts new differentiation conditions yielding hormonally responsive iADIPO are derived. Through concomitant optimization of an iADIPO‐MPS, it is abled to obtain WAT with more unilocular and significantly larger (≈40%) lipid droplets compared to iADIPO in 2D culture, increased insulin responsiveness of glucose uptake (≈2–3 fold), fatty acid uptake (≈3–6 fold), and ≈40% suppressing of stimulated lipolysis giving a dynamic range that is competent to current in vivo and ex vivo models, allowing to identify both insulin sensitizers and desensitizers.
This study uses human stem cells to derive metabolically functional 3D adipose tissue in a microphysiological system. Through concomitant optimization, the adipose system shows mostly unilocular and significantly larger lipid droplets, increased insulin responsiveness of glucose uptake, fatty acid uptake, and suppressing of stimulated lipolysis compared to 2D culture, providing a good dynamic range to identify insulin sensitizers and desensitizers.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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