Project description:Immune cells in visceral adipose tissue are critical for regulating metabolic homeostasis. In addition, gut microbiota is an important regulator of the immune system. We used single-cell RNA sequencing (scRNA-seq) to analyze the relationship between gut microbiota and immune cells in visceral adipose tissue.
Project description:Interplay between parenchymal energy-storing white adipose cells and thermogenic beige adipocytes contributes to obesity and insulin resistance. Irrespective of cellular origin or specialized niche, adipocytes require the activity of the nuclear receptor peroxisome proliferator activated receptor gamma (PPARγ) for proper function. Exposure to cold or adrenergic signaling enriches thermogenic cells though multiple pathways that act synergistically with PPARγ, however, the molecular mechanisms by which PPARγ licenses white adipose tissue (WAT) to preferentially adopt a thermogenic or white adipose fate in response to dietary cues or thermoneutral conditions are not fully elucidated. Here, we show that a PPARγ-long noncoding RNA (lncRNA) axis integrates canonical and noncanonical thermogenesis to restrain white adipose tissue heat dissipation during thermoneutrality and diet-induced obesity (DIO). Pharmacologic inhibition or genetic deletion of the lncRNA Lexis, enhances UCP-1 dependent and independent thermogenesis. Adipose tissue specific deletion of Lexis counteracted diet-induced obesity, improved insulin sensitivity, and enhanced energy expenditure. Single-nuclei transcriptomics revealed that Lexis regulates a distinct population of thermogenic adipocytes. We systematically map Lexis motif preferences and show that it regulates the thermogenic program through the activity of the metabolic GWAS gene and WNT modulator TCF7L2. Collectively, our studies uncover a new mode of crosstalk between PPARγ and WNT signaling that preserves white adipose tissue plasticity.
Project description:Interplay between parenchymal energy-storing white adipose cells and thermogenic beige adipocytes contributes to obesity and insulin resistance. Irrespective of cellular origin or specialized niche, adipocytes require the activity of the nuclear receptor peroxisome proliferator activated receptor gamma (PPARγ) for proper function. Exposure to cold or adrenergic signaling enriches thermogenic cells though multiple pathways that act synergistically with PPARγ, however, the molecular mechanisms by which PPARγ licenses white adipose tissue (WAT) to preferentially adopt a thermogenic or white adipose fate in response to dietary cues or thermoneutral conditions are not fully elucidated. Here, we show that a PPARγ-long noncoding RNA (lncRNA) axis integrates canonical and noncanonical thermogenesis to restrain white adipose tissue heat dissipation during thermoneutrality and diet-induced obesity (DIO). Pharmacologic inhibition or genetic deletion of the lncRNA Lexis, enhances UCP-1 dependent and independent thermogenesis. Adipose tissue specific deletion of Lexis counteracted diet-induced obesity, improved insulin sensitivity, and enhanced energy expenditure. Single-nuclei transcriptomics revealed that Lexis regulates a distinct population of thermogenic adipocytes. We systematically map Lexis motif preferences and show that it regulates the thermogenic program through the activity of the metabolic GWAS gene and WNT modulator TCF7L2. Collectively, our studies uncover a new mode of crosstalk between PPARγ and WNT signaling that preserves white adipose tissue plasticity.
Project description:We identify fibroblast growth factor 1 (FGF1) as a critical transducer in adipose tissue remodeling and link its regulation to peroxisome proliferator activated-receptor γ (PPARγ), the adipocyte master regulator and target of the thiazolidinedione (TZD) class of insulin sensitizing drugs. We show that FGF1 is highly induced in adipose tissue in response to high-fat diet (HFD) and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with HFD. Mechanistically, we show that transcription of FGF1 is directly regulated by an adipocyte-selective proximal PPAR response element, and that this PPARγ-FGF1 axis is evolutionarily conserved in mammals. This work describes the first phenotype of the FGF1 knockout mouse and establishes FGF1 as a new member of the NR-FGF axis critical for maintaining metabolic homeostasis and insulin sensitization.
Project description:Interplay between parenchymal energy-storing white adipose cells and thermogenic beige adipocytes contributes to obesity and insulin resistance. Irrespective of cellular origin or specialized niche, adipocytes require the activity of the nuclear receptor peroxisome proliferator activated receptor gamma (PPARγ) for proper function. Exposure to cold or adrenergic signaling enriches thermogenic cells though multiple pathways that act synergistically with PPARγ, however, the molecular mechanisms by which PPARγ licenses white adipose tissue (WAT) to preferentially adopt a thermogenic or white adipose fate in response to dietary cues or thermoneutral conditions are not fully elucidated. Here, we show that a PPARγ-long noncoding RNA (lncRNA) axis integrates canonical and noncanonical thermogenesis to restrain white adipose tissue heat dissipation during thermoneutrality and diet-induced obesity (DIO). Pharmacologic inhibition or genetic deletion of the lncRNA Lexis, enhances UCP-1 dependent and independent thermogenesis. Adipose tissue specific deletion of Lexis counteracted diet-induced obesity, improved insulin sensitivity, and enhanced energy expenditure. Single-nuclei transcriptomics revealed that Lexis regulates a distinct population of thermogenic adipocytes. We systematically map Lexis motif preferences and show that it regulates the thermogenic program through the activity of the metabolic GWAS gene and WNT modulator TCF7L2. Collectively, our studies uncover a new mode of crosstalk between PPARγ and WNT signaling that preserves white adipose tissue plasticity.
Project description:The balance between tolerogenic and inflammatory responses determines immune homeostasis in the gut. Dysbiosis and a defective host defense against invading intestinal bacteria can shift this balance via bacterial-derived metabolites and trigger chronic inflammation. We show that the short chain fatty acid butyrate modulates monocyte to macrophage differentiation by promoting antimicrobial effector functions. The presence of butyrate modulates antimicrobial activity via a shift in macrophage metabolism and reduction in mTOR activity. This mechanism is furthermore dependent on the inhibitory function of butyrate on histone deacetylase 3 (HDAC3) driving transcription of a set of antimicrobial peptides including calprotectin. The increased antimicrobial activity against several bacterial species is not associated with increased production of conventional cytokines. Butyrate imprints antimicrobial activity of intestinal macrophages in vivo. Our data suggest that commensal bacteria derived butyrate stabilize gut homeostasis by promoting antimicrobial host defense pathways in monocytes that differentiate into intestinal macrophages.