Project description:Active thermogenic adipocytes voraciously consume energy substrates like fatty acids and glucose to maintain body temperature upon cold exposure. Despite strong evidence for the involvement of brown adipose tissue (BAT) in controlling systemic energy homeostasis upon nutrient excess, it is unclear how the activity of brown adipocytes is regulated in times of nutrient scarcity. Therefore, this study aimed to scrutinize factors that modulate BAT activity to balance thermogenic and energetic needs upon simultaneous fasting and cold-exposure. For an unbiased view we performed transcriptomic and miRNA sequencing analysis of BAT from acutely fasted (24 hours) mice under mild cold exposure. Combining these data with in-depth bioinformatic analyses and in vitro experiments, we defined a previously undescribed axis of p53 and miR-92a-1-5p that is highly upregulated by fasting in thermogenic adipocytes. p53, a fasting-responsive transcription factor, was previously shown to control genes involved in the thermogenic program and miR-92a-1-5p was found to negatively correlate with human BAT activity. Here, we elucidated fructose transporter Slc2a5 as one direct downstream target of this axis and show that fructose can be taken up by and metabolized in brown adipocytes. In sum, this study delineates a fasting-induced pathway involving p53 and miR-92a-1-5p impinging on Slc2a5 and suggests a contribution of fructose as an energy substrate in thermogenic adipocytes.
Project description:In obesity, sustained adipose tissue (AT) inflammation constitutes a cellular memory that limits the effectiveness of weight loss interventions. Yet, its fasting regimen-dependent regulation is unknown. Here, we show that cyclic intermittent fasting (IF) exacerbates the lipid-associated macrophage (LAM) inflammatory phenotype of visceral AT in obese mice. Importantly, we provide evidence that this increase in LAM abundance is almost entirely dependent on p53-driven adipocyte apoptosis. Adipocyte-specific deletion of p53 prevents LAM accumulation in AT during IF and increases the catabolic state of adipocytes, ameliorates metabolic flexibility, and insulin sensitivity. Finally, in cohorts of obese/diabetic patients, we describe a p53 polymorphism that links to long-term efficacy of a fasting-mimicking diet and that the expression of LAM markers and p53 in AT negatively correlates with maintaining weight loss after bariatric surgery. Overall, our results demonstrate that p53 signaling in adipocytes dictates LAM accumulation in AT under IF and that adipocyte p53 modulates fasting effectiveness in mice and humans.
Project description:In obesity, sustained adipose tissue (AT) inflammation constitutes a cellular memory that limits the effectiveness of weight loss interventions. Yet, its fasting regimen-dependent regulation is unknown. Here, we show that cyclic intermittent fasting (IF) exacerbates the lipid-associated macrophage (LAM) inflammatory phenotype of visceral AT in obese mice. Importantly, we provide evidence that this increase in LAM abundance is almost entirely dependent on p53-driven adipocyte apoptosis. Adipocyte-specific deletion of p53 prevents LAM accumulation in AT during IF and increases the catabolic state of adipocytes, ameliorates metabolic flexibility, and insulin sensitivity. Finally, in cohorts of obese/diabetic patients, we describe a p53 polymorphism that links to long-term efficacy of a fasting-mimicking diet and that the expression of LAM markers and p53 in AT negatively correlates with maintaining weight loss after bariatric surgery. Overall, our results demonstrate that p53 signaling in adipocytes dictates LAM accumulation in AT under IF and that adipocyte p53 modulates fasting effectiveness in mice and humans.
Project description:We report bulk RNA-sequencing of brown adipose tissue (BAT) harvested from K15flox/flox and BAT specific KLF15 knockout (K15-BKO) mice in response to cold challenge and fasting
Project description:Cancer cells voraciously consume nutrients to support their growth, exposing a metabolic vulnerability that can be therapeutically exploited. Here we show in hepatocellular carcinoma (HCC) cells, xenografts, and in patient-derived HCC organoids that fasting can synergistically sensitise resistant HCC to sorafenib. Mechanistically, sorafenib acts non-canonically as inhibitor of mitochondrial respiration, causing resistant cells to depend on glycolysis for survival. Fasting, through reduction in glucose and impeded AKT/mTOR-signalling, prevents this Warburg shift. p53 is necessary and sufficient for the sorafenib-sensitizing effect of nutrient restriction and crucial for improvement of sorafenib efficacy through intermittent fasting (IF) in an orthotopic HCC mouse model. Together, our data indicate IF and sorafenib as clinically actionable, rational combination therapy for HCC with intact p53 signalling. As HCC therapy is currently severely limited by resistance, these results should instigate clinical studies with the goal of improving therapy response in advanced-stage, and possibly even early-stage, HCC.
Project description:PGE2/EP3 signaling and m6A modification is required for brown adipocyte differentiation and BAT development, but the underlying mechanisms involved remain to be elucidated. The Arraystar mousen M6a-MRNA&lncRNA Epitranscriptomic microarray analysis was performed on mouse brown preadipocytes with or without EP3 deletion.
Project description:The functional balance between brown adipose tissue (BAT) and white adipose tissue (WAT) is important for metabolic homeostasis. We compared the effects of fasting on the gene expression profiles in BAT, WAT and liver, using DNA microarray analysis. Tissues were obtained from rats that had been fed or fasted for 24 h. Taking the false discovery rate (FDR) into account, we extracted the top 1,000 genes that were expressed differentially between fed and fasted rats. In all three tissues, Gene Ontology analysis revealed marked changes in the expression of ‘metabolism’ category genes and a hypergeometric test demonstrated that within this category, lipid and protein biosynthesis-related genes were down-regulated. These findings indicate simultaneous down-regulation of genes involved in energy-consuming pathways in the BAT, WAT and liver of fasted rats. In the BAT of fasted rats, there was marked up-regulation of genes in the ‘protein ubiquitination’ category, suggesting that the ubiquitin-proteasome system is involved in saving energy as an adaptation to food shortage. Keywords: treatment comparison
Project description:Rdh1 is one of the several enzymes that catalyze the first of the two reactions to convert retinol into all-trans-retinoic acid (atRA). Here we show that Rdh1-null mice fed low-fat diet gain more weight as adiposity thann wild-type mice by 20 weeks old, despite neither consuming more calories nor decreasing activity. RNAseq revealed dysregulation of 424 BAT genes in null mice, with segregated predominantly into differences after fasting vs after re-feeding. Rdh1-generated atRA in BAT regulates multiple genes that promote BAT adaptation to whole-body energy status, such as fasting and re-feeding.