Age-associated insulin resistance (IR) and obesity-associated IR are two physiologically distinct forms of adult-onset diabetes. While macrophage-driven inflammation is a core driver of ...obesity-associated IR, the underlying mechanisms of the obesity-independent yet highly prevalent age-associated IR are largely unexplored. Here we show, using comparative adipo-immune profiling in mice, that fat-resident regulatory T cells, termed fTreg cells, accumulate in adipose tissue as a function of age, but not obesity. Supporting the existence of two distinct mechanisms underlying IR, mice deficient in fTreg cells are protected against age-associated IR, yet remain susceptible to obesity-associated IR and metabolic disease. By contrast, selective depletion of fTreg cells via anti-ST2 antibody treatment increases adipose tissue insulin sensitivity. These findings establish that distinct immune cell populations within adipose tissue underlie ageing- and obesity-associated IR, and implicate fTreg cells as adipo-immune drivers and potential therapeutic targets in the treatment of age-associated IR.
A common thread among conserved life span regulators lies within intertwined roles in metabolism and energy homeostasis. We show that heterozygous mutations of AMP biosynthetic enzymes extend ...Drosophila life span. The life span benefit of these mutations depends upon increased AMP:ATP and ADP:ATP ratios and adenosine monophosphate-activated protein kinase (AMPK). Transgenic expression of AMPK in adult fat body or adult muscle, key metabolic tissues, extended life span, while AMPK RNAi reduced life span. Supplementing adenine, a substrate for AMP biosynthesis, to the diet of long-lived AMP biosynthesis mutants reversed life span extension. Remarkably, this simple change in diet also blocked the prolongevity effects of dietary restriction. These data establish AMP biosynthesis, adenosine nucleotide ratios, and AMPK as determinants of adult life span; provide a mechanistic link between cellular anabolism and energy sensing pathways; and indicate that dietary adenine manipulations might alter metabolism to influence animal life span.
► Heterozygous AMP biosynthesis mutations act via AMPK to extend life span ► Tissue- and adult-specific transgenic expression of AMPK extends life span ► Dietary adenine reverses the life span extension of adult AMP biosynthesis mutants ► Addition of dietary adenine blocks the longevity effects of dietary restriction
Secretory proteins are an essential component of interorgan communication networks that regulate animal physiology. Current approaches for identifying secretory proteins from specific cell and tissue ...types are largely limited to in vitro or ex vivo models which often fail to recapitulate in vivo biology. As such, there is mounting interest in developing in vivo analytical tools that can provide accurate information on the origin, identity, and spatiotemporal dynamics of secretory proteins. Here, we describe iSLET (in situ Secretory protein Labeling via ER-anchored TurboID) which selectively labels proteins that transit through the classical secretory pathway via catalytic actions of Sec61b-TurboID, a proximity labeling enzyme anchored in the ER lumen. To validate iSLET in a whole-body system, we express iSLET in the mouse liver and demonstrate efficient labeling of liver secretory proteins which could be tracked and identified within circulating blood plasma. Furthermore, proteomic analysis of the labeled liver secretome enriched from liver iSLET mouse plasma is highly consistent with previous reports of liver secretory protein profiles. Taken together, iSLET is a versatile and powerful tool for studying spatiotemporal dynamics of secretory proteins, a valuable class of biomarkers and therapeutic targets.
Disclosure
K.Kim: None. J.Suh: None.
Funding
National Research Foundation of Korea (2018R1A2A3075389, 2016M3A9B6902871, 2017K1A1A2013124, 2021R1A2C2007573, 2020R1C1C1013927); KAIST Key Research Institutes Project; Bio and Medical Technology Development Program (2019M3E5D3073104); Ministry of Science
White adipose (fat) tissues regulate metabolism, reproduction, and life span. Adipocytes form throughout life, with the most marked expansion of the lineage occurring during the postnatal period. ...Adipocytes develop in coordination with the vasculature, but the identity and location of white adipocyte progenitor cells in vivo are unknown. We used genetically marked mice to isolate proliferating and renewing adipogenic progenitors. We found that most adipocytes descend from a pool of these proliferating progenitors that are already committed, either prenatally or early in postnatal life. These progenitors reside in the mural cell compartment of the adipose vasculature, but not in the vasculature of other tissues. Thus, the adipose vasculature appears to function as a progenitor niche and may provide signals for adipocyte development.
Abstract
Secretory proteins are an essential component of interorgan communication networks that regulate animal physiology. Current approaches for identifying secretory proteins from specific cell ...and tissue types are largely limited to in vitro or ex vivo models which often fail to recapitulate in vivo biology. As such, there is mounting interest in developing in vivo analytical tools that can provide accurate information on the origin, identity, and spatiotemporal dynamics of secretory proteins. Here, we describe
i
SLET (in situ Secretory protein Labeling via ER-anchored TurboID) which selectively labels proteins that transit through the classical secretory pathway via catalytic actions of Sec61b-TurboID, a proximity labeling enzyme anchored in the ER lumen. To validate
i
SLET in a whole-body system, we express
i
SLET in the mouse liver and demonstrate efficient labeling of liver secretory proteins which could be tracked and identified within circulating blood plasma. Furthermore, proteomic analysis of the labeled liver secretome enriched from liver
i
SLET mouse plasma is highly consistent with previous reports of liver secretory protein profiles. Taken together,
i
SLET is a versatile and powerful tool for studying spatiotemporal dynamics of secretory proteins, a valuable class of biomarkers and therapeutic targets.
Nonalcoholic fatty liver disease (NAFLD) is increasing in worldwide prevalence, closely tracking the obesity epidemic, but specific pharmaceutical treatments for NAFLD are lacking. Defining the key ...molecular pathways underlying the pathogenesis of NAFLD is essential for developing new drugs. Here we demonstrate that inhibition of gut-derived serotonin synthesis ameliorates hepatic steatosis through a reduction in liver serotonin receptor 2A (HTR2A) signaling. Local serotonin concentrations in the portal blood, which can directly travel to and affect the liver, are selectively increased by high-fat diet (HFD) feeding in mice. Both gut-specific Tph1 knockout mice and liver-specific Htr2a knockout mice are resistant to HFD-induced hepatic steatosis, without affecting systemic energy homeostasis. Moreover, selective HTR2A antagonist treatment prevents HFD-induced hepatic steatosis. Thus, the gut TPH1-liver HTR2A axis shows promise as a drug target to ameliorate NAFLD with minimal systemic metabolic effects.
Adipose tissue regulates systemic energy homeostasis by acting as an energy reservoir and endocrine organ. Coordinated regulation of these functions is essential for metabolic health, but the ...underlying mechanisms are unknown. Here we show that the transcriptional coregulators YAP and TAZ mediate the crosstalk between adipose tissue mass and leptin levels to maintain systemic energy balance. The activation of adipocyte-specific YAP/TAZ via genetic ablation of the upstream regulators LATS1 and LATS2 resulted in a profound reduction in fat mass due to the conversion of mature adipocytes into delipidated cells with progenitor-like features. Rosiglitazone treatment normalized fat mass, indicating that PPARG inhibition is a major contributor to YAP/TAZ-induced lipoatrophy. Surprisingly, LATS1/2 knockout mice did not exhibit lipodystrophy-related metabolic dysfunction. This phenotype was attributed to a paradoxical increase in circulating leptin levels, which was found to offset the energy storage deficit by increasing fat oxidation and energy expenditure. Mechanistically, we identify a YAP/TAZ-TEAD axis that upregulates leptin expression by direct binding to an upstream enhancer site of the leptin gene. Finally, we show that YAP/TAZ activity is associated with leptin regulation during fasting and refeeding, indicating that YAP/TAZ links nutrient status in adipose tissue to systemic energy homeostasis. Taken together, we reveal that adipocyte Hippo-YAP/TAZ functions as a nexus for coordinating nutrient storage capacity and systemic energy balance by regulating adipocyte plasticity and leptin gene transcription.
Disclosure
S.Choi: None. K.Park: None. H.Shin: None. J.Suh: None.
Obesity and aging are major risk factors for various diseases and thus represent heavy socioeconomic burden to global healthcare. The two processes share similar, if not convergent, phenotypes, and ...increasing evidence suggests that one accelerates the other. Both obesity and aging are associated with insulin resistance, chronic low-grade inflammation and dysfunction of systemic energy homeostasis. However, there are many differences as well and the molecular mechanisms behind such similarities and differences remain unclear. Dysfunction of adipose tissue plays a significant role in both processes. Many studies have characterized adipose tissue of lean and obese mice at single-cell level, but obese and aged adipose tissue have not been directly compared side-by-side. Here, we compare single-cell transcriptomics of visceral (VAT) and subcutaneous (SAT) white adipose tissue in lean, diet-induced obesity, and aged conditions. In obese VAT, the relative frequency of macrophages increased, while that of lymphocytes decreased as expected. However, such myeloid shift was not observed in aged VAT. Metabolically, TREM2+ “lipid-associated macrophages”, which is known to increase in obese VAT, did not increase in aged VAT. Clustering of mesenchymal progenitor cells revealed depot-specific differences in previously reported cell subtypes. More cells were in a further differentiated, committed stage in VAT than in SAT. CD142+ CLEC11A+ “Aregs,” which were previously found to inhibit adipogenesis, increased in aged VAT and obese SAT. Interestingly, the frequency of endothelial cells in obese or aged state drastically decreased in SAT but not in VAT. Our comparative single-cell transcriptome atlas provides a detailed resource to analyze functional genomics behind obesity and aging.
Disclosure
E.Lee: None. D.Kang: None. J.Suh: None.
Brown adipose tissue (BAT) plays a key role in the regulated production of heat in response to cold temperatures, known as adaptive thermogenesis. While the transcriptional mechanisms underlying the ...thermogenic function of BAT has been widely studied, the role of posttranscriptional processes in BAT thermogenesis remain largely unexplored. RNA binding proteins are central to the control multiple aspects of posttranscriptional RNA biology. Here, we identify brown fat HuR as a critical regulator of adaptive thermogenesis. Mice with adipocyte-specific HuR deletion (AKO) were unable to increase energy expenditure in response to a cold challenge, resulting in marked hypothermia. HuR AKO mice housed at thermoneutrality also failed to increase energy expenditure upon beta-3 adrenoreceptor agonist treatment, indicating a defect in thermogenic BAT. HuR-deleted brown adipocytes displayed impaired mitochondrial respiration under β-adrenergic stimulation. RNA sequencing data revealed that loss of HuR led to downregulation of genes associated with TCA cycle, β-oxidation, and mTORC1 signaling in BAT. Our findings reveal an essential role for RNA binding protein HuR in thermogenic programs of the brown adipocyte and highlight the importance of posttranscriptional processes in BAT thermogenesis.
Disclosure
K.Park: None. S.Choi: None. J.Suh: None.
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