Mechanisms and Metabolic Implications of Regional Differences among Fat Depots

Tchkonia, Tamar; Thomou, Thomas; Zhu, Yi; Καραγιαννίδης, Ιορδάνης; Pothoulakis, Charalabos; Jensen, Michael D.; Kirkland, James L.

doi:10.1016/j.cmet.2013.03.008

Cited by 564 publications

(531 citation statements)

References 141 publications

(237 reference statements)

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“…Supporting this view is the finding that isolated preadipocytes exhibit intrinsic differences in many functional characteristics, including proliferation, apoptosis, and adipogenesis (12). Transcriptional profiling has also identified unique regional mRNA profiles characterized by differential expression of developmental genes (13)(14)(15), some of which correlate with obesity (HOXA5, TBX15) (16) and appear to be important regulators of adipocyte development and function (SHOX2, TBX15) (17,18).…”

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confidence: 75%

Distinct Developmental Profile of Lower-Body Adipose Tissue Defines Resistance Against Obesity-Associated Metabolic Complications

et al. 2014

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Upper-and lower-body fat depots exhibit opposing associations with obesity-related metabolic disease. We defined the relationship between DEXA-quantified fat depots and diabetes/cardiovascular risk factors in a healthy population-based cohort (n = 3,399). Gynoid fat mass correlated negatively with insulin resistance after total fat mass adjustment, whereas the opposite was seen for abdominal fat. Paired transcriptomic analysis of gluteal subcutaneous adipose tissue (GSAT) and abdominal subcutaneous adipose tissue (ASAT) was performed across the BMI spectrum (n = 49; 21.4-45.5 kg/m 2 ). In both depots, energy-generating metabolic genes were negatively associated and inflammatory genes were positively associated with obesity. However, associations were significantly weaker in GSAT. At the systemic level, arteriovenous release of the proinflammatory cytokine interleukin-6 (n = 34) was lower from GSAT than ASAT. Isolated preadipocytes retained a depotspecific transcriptional "memory" of embryonic developmental genes and exhibited differential promoter DNA methylation of selected genes (HOTAIR, TBX5) between GSAT and ASAT. Short hairpin RNA-mediated silencing identified TBX5 as a regulator of preadipocyte proliferation and adipogenic differentiation in ASAT. In conclusion, intrinsic differences in the expression of developmental genes in regional adipocytes provide a mechanistic basis for diversity in adipose tissue (AT) function. The less inflammatory nature of lower-body AT offers insight into the opposing metabolic disease risk associations between upper-and lower-body obesity.Lower-body fat accumulation, as opposed to central obesity, is inversely associated with metabolic risk factors, including hyperinsulinemia, dyslipidemia, and hypertension (1), and is also associated with a reduced incidence of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) (2,3). Conversely, loss of lower-body fat during weight reduction relates to adverse changes in blood lipid and glucose profiles as well as blood pressure (4).

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confidence: 75%

Distinct Developmental Profile of Lower-Body Adipose Tissue Defines Resistance Against Obesity-Associated Metabolic Complications

et al. 2014

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“…Meanwhile, evidence has shown a depot difference in the productions of inflammatory cytokines and adipokines. For example, the expressions of cytokines such as interleukin 6 (IL-6), MCP1, and adiponectin are higher in visceral fat tissue, whereas the expression of leptin is higher in subcutaneous adipose tissue (Tchkonia et al, 2013). A recent study demonstrated that gluteal subcutaneous adipose tissue (GSAT) had less inflammatory profiles than abdominal subcutaneous adipose tissue (ASAT).…”

Section: Introductionmentioning

confidence: 99%

Effects of a multi-component camp-based intervention on inflammatory markers and adipokines in children: A randomized controlled trial

Huang

Larsen

Møller

et al. 2015

Preventive Medicine

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This file was dowloaded from the institutional repository Brage NIH -brage.bibsys.no/nih Huang, T., Larsen, K. T., Møller, N. C., Ried-Larsen, M., Frandsen, U., Andersen, L. B. (2015 Methods:One hundred and fifteen children were recruited in Odense, Denmark (2011Denmark ( -2014. The participants were randomly allocated to either the day camp intervention arm (DCIA) or the standard intervention arm (SIA). The intervention for the DCIA comprised a 6-week camp intervention and a 46-week family-based intervention. The SIA was offered one weekly physical activity session for 6 weeks and one educational meeting. C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP1), leptin, and adiponectin were measured in serum at baseline, 6 weeks and 52 weeks.Results: Compared with the SIA, the reductions in CRP (P=0.003) and leptin (p<0.001) were larger in the DCIA at 6 weeks. The intervention effects on leptin were significantly mediated by the changes in body fat mass. No intervention effects on CRP and leptin were seen at 52 weeks. No between-group differences in changes in MCP1 and adiponectin were observed at 6 weeks or 52 weeks. Conclusions:The 6-week camp intervention resulted in reductions in CRP and leptin. The intervention effects did not persist to 52 weeks. The intervention effect on leptin was explained by the changes in body fat mass.

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“…Preadipocytes, also termed "adipose-derived stem cells" or "fat cell progenitors" (38), constitute 15-50% of the cells in adipose tissue and arguably are the most abundant progenitor cell type in humans (39). We first tested whether the number of senescent preadipocytes increases in adipose tissue with aging.…”

Section: Significancementioning

confidence: 99%

JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

Tchkonia

Ding

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction.JAK/STAT pathway | cellular senescence | ruxolitinib | interleukin-6 | frailty

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Mechanisms and Metabolic Implications of Regional Differences among Fat Depots

Cited by 564 publications

References 141 publications

Distinct Developmental Profile of Lower-Body Adipose Tissue Defines Resistance Against Obesity-Associated Metabolic Complications

Distinct Developmental Profile of Lower-Body Adipose Tissue Defines Resistance Against Obesity-Associated Metabolic Complications

Effects of a multi-component camp-based intervention on inflammatory markers and adipokines in children: A randomized controlled trial

JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

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