Adipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape.

In obesity, sustained adipose tissue (AT) inflammation constitutes a cellular memory that limits the effectiveness of weight loss interventions. Yet, the impact of fasting regimens on the regulation of AT immune infiltration is still elusive. Here we show that intermittent fasting (IF) exacerbates the lipid-associated macrophage (LAM) inflammatory phenotype of visceral AT in obese mice.

Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism.

Accumulation of excess nutrients hampers proper liver function and is linked to nonalcoholic fatty liver disease (NAFLD) in obesity. However, the signals responsible for an impaired adaptation of hepatocytes to obesogenic dietary cues remain still largely unknown. Post-translational modification by the small ubiquitin-like modifier (SUMO) allows for a dynamic regulation of numerous processes including transcriptional reprogramming.

Adipocyte-specific tribbles pseudokinase 1 regulates plasma adiponectin and plasma lipids in mice.

Objective: Multiple genome-wide association studies (GWAS) have identified SNPs in the 8q24 locus near TRIB1 that are significantly associated with plasma lipids and other markers of cardiometabolic health, and prior studies have revealed the roles of hepatic and myeloid Trib1 in plasma lipid regulation and atherosclerosis. The same 8q24 SNPs are additionally associated with plasma adiponectin levels in humans, implicating TRIB1 in adipocyte biology. Here, we hypothesize that TRIB1 in adipose tissue regulates plasma adiponectin, lipids, and metabolic health.

WITHDRAWN: Adipocyte Deletion of ADAM17 Leads to Insulin Resistance in Association with Age and HFD in Mice.

Withdrawal: Valeria Lopez Salazar, Rhoda Anane Karikari, Lun Li, Rabih El-Merahbi, Maria Troullinaki, Moya Wu, Tobias Wiedemann, Alina Walth, Manuel Gil Lozano, Maria Rohm, Stephan Herzig, Anastasia Georgiadi. Adipocyte Deletion of ADAM17 Leads to Insulin Resistance in Association with Age and HFD in Mice (2021). The FASEB Journal.

Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue.

The proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis.

Lipocalin 13 enhances insulin secretion but is dispensable for systemic metabolic control.

Members of the lipocalin protein family serve as biomarkers for kidney disease and acute phase inflammatory reactions, and are under preclinical development for the diagnosis and therapy of allergies. However, none of the lipocalin family members has made the step into clinical development, mostly due to their complex biological activity and the lack of in-depth mechanistic knowledge. Here, we show that the hepatokine lipocalin 13 (LCN13) triggers glucose-dependent insulin secretion and cell proliferation of primary mouse islets.

HILPDA Uncouples Lipid Droplet Accumulation in Adipose Tissue Macrophages from Inflammation and Metabolic Dysregulation.

Obesity leads to a state of chronic, low-grade inflammation that features the accumulation of lipid-laden macrophages in adipose tissue. Here, we determined the role of macrophage lipid-droplet accumulation in the development of obesity-induced adipose-tissue inflammation, using mice with myeloid-specific deficiency of the lipid-inducible HILPDA protein. HILPDA deficiency markedly reduced intracellular lipid levels and accumulation of fluorescently labeled fatty acids.

The role of brown and beige adipose tissue in glycaemic control.

For the past decade, brown adipose tissue (BAT) has been extensively studied as a potential therapy for obesity and metabolic diseases due to its thermogenic and glucose-consuming properties. It is now clear that the function of BAT goes beyond heat production, as it also plays an important endocrine role by secreting the so-called batokines to communicate with other metabolic tissues and regulate systemic energy homeostasis. However, despite numerous studies showing the benefits of BAT in rodents, it is still not clear whether recruitment of BAT can be utilized to treat human patients.

Endocrine and autocrine/paracrine modulators of brown adipose tissue mass and activity as novel therapeutic strategies against obesity and type 2 diabetes.

The dramatically increasing world-wide prevalence of obesity is recognized as a risk factor for the development of various diseases. The growing research on the role of adipose tissue in controlling energy homeostasis and insulin sensitivity has revealed that the promotion of brown adipose tissue (BAT) activity and the browning of white adipose tissue (WAT) leads to multiple health benefits and prevents obesity and type 2 diabetes (T2D). Inducible thermogenic adipocytes do exist in adult humans and are linked with increased energy combustion and lower body fat mass.

Lsd1 prevents age-programed loss of beige adipocytes.

Aging is accompanied by major changes in adipose tissue distribution and function. In particular, with time, thermogenic-competent beige adipocytes progressively gain a white adipocyte morphology. However, the mechanisms controlling the age-related transition of beige adipocytes to white adipocytes remain unclear.

FNDC4 acts as an anti-inflammatory factor on macrophages and improves colitis in mice.

FNDC4 is a secreted factor sharing high homology with the exercise-associated myokine irisin (FNDC5). Here we report that Fndc4 is robustly upregulated in several mouse models of inflammation as well as in human inflammatory conditions. Specifically, FNDC4 levels are increased locally at inflamed sites of the intestine of inflammatory bowel disease patients.

Inflammation increases plasma angiopoietin-like protein 4 in patients with the metabolic syndrome and type 2 diabetes.

Background: Angiopoietin-like protein 4 (ANGPTL4) inhibits lipoprotein lipase and associates with dyslipidemia. The expression of ANGPTL4 is regulated by free fatty acids (FFA) that activate lipid-sensing peroxisome proliferator-activated receptors (PPARs), but FFA can also activate pattern recognition receptors including Toll-like receptor 4 (TLR4) in macrophages.

Objective: To assess whether systemic low-grade inflammation is a determinant for plasma ANGPTL4 levels in patients with the metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM).

Hypoxia-inducible lipid droplet-associated (HILPDA) is a novel peroxisome proliferator-activated receptor (PPAR) target involved in hepatic triglyceride secretion.

Peroxisome proliferator-activated receptors (PPARs) play major roles in the regulation of hepatic lipid metabolism through the control of numerous genes involved in processes such as lipid uptake and fatty acid oxidation. Here we identify hypoxia-inducible lipid droplet-associated (Hilpda/Hig2) as a novel PPAR target gene and demonstrate its involvement in hepatic lipid metabolism. Microarray analysis revealed that Hilpda is one of the most highly induced genes by the PPARα agonist Wy14643 in mouse precision cut liver slices.

β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors.

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) regulates metabolic genes in skeletal muscle and contributes to the response of muscle to exercise. Muscle PGC-1α transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1α-mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined.

Impact of exercise on muscle and nonmuscle organs.

Exercise is known to prevent and treat metabolic diseases such as diabetes. However, the underlying mechanisms are not fully understood, and there is currently much focus on detailing such pathways. Traditionally, much emphasis has been placed on skeletal muscle; however, recently, nonmuscle organs such as adipose tissue have been highlighted in mediating protective actions after training.

Overexpression of angiopoietin-like protein 4 protects against atherosclerosis development.

Objective: Macrophage foam cells play a crucial role in several pathologies including multiple sclerosis, glomerulosclerosis, and atherosclerosis. Angiopoietin-like protein 4 (Angptl4) was previously shown to inhibit chyle-induced foam cell formation in mesenteric lymph nodes. Here we characterized the regulation of Angptl4 expression in macrophages and examined the impact of Angptl4 on atherosclerosis development.

Mechanisms of gene regulation by fatty acids.

Consumption of specific dietary fatty acids has been shown to influence risk and progression of several chronic diseases, such as cardiovascular disease, obesity, cancer, and arthritis. In recent years, insights into the mechanisms underlying the biological effects of fatty acids have improved considerably and have provided the foundation for the emerging concept of fatty acid sensing, which can be interpreted as the property of fatty acids to influence biological processes by serving as signaling molecules. An important mechanism of fatty acid sensing is via stimulation or inhibition of DNA transcription.

Detailed transcriptomics analysis of the effect of dietary fatty acids on gene expression in the heart.

Fatty acids comprise the primary energy source for the heart and are mainly taken up via hydrolysis of circulating triglyceride-rich lipoproteins. While most of the fatty acids entering the cardiomyocyte are oxidized, a small portion is involved in altering gene transcription to modulate cardiometabolic functions. So far, no in vivo model has been developed enabling study of the transcriptional effects of specific fatty acids in the intact heart.

Energy-sensing factors coactivator peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and AMP-activated protein kinase control expression of inflammatory mediators in liver: induction of interleukin 1 receptor antagonist.

Obesity and insulin resistance are associated with chronic, low grade inflammation. Moreover, regulation of energy metabolism and immunity are highly integrated. We hypothesized that energy-sensitive coactivator peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and AMP-activated protein kinase (AMPK) may modulate inflammatory gene expression in liver.

Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages.

Dietary saturated fat is linked to numerous chronic diseases, including cardiovascular disease. Here we study the role of the lipoprotein lipase inhibitor Angptl4 in the response to dietary saturated fat. Strikingly, in mice lacking Angptl4, saturated fat induces a severe and lethal phenotype characterized by fibrinopurulent peritonitis, ascites, intestinal fibrosis, and cachexia.

Induction of cardiac Angptl4 by dietary fatty acids is mediated by peroxisome proliferator-activated receptor beta/delta and protects against fatty acid-induced oxidative stress.

Rationale: Although dietary fatty acids are a major fuel for the heart, little is known about the direct effects of dietary fatty acids on gene regulation in the intact heart.

Objective: To study the effect of dietary fatty acids on cardiac gene expression and explore the functional consequences.

Methods And Results: Oral administration of synthetic triglycerides composed of one single fatty acid altered cardiac expression of numerous genes, many of which are involved in the oxidative stress response.