Adiponectin overexpression improves metabolic abnormalities caused by acid ceramidase deficiency but does not prolong lifespan in a mouse model of Farber Disease

Farber Disease is a debilitating and lethal childhood disease of ceramide accumulation caused by acid ceramidase deficiency. The potent induction of a ligand-gated neutral ceramidase activity promoted by adiponectin may provide sufficient lowering of ceramides to allow for the treatment of Farber Disease. In vitro, adiponectin or adiponectin receptor agonist treatments lowered total ceramide concentrations in human fibroblasts from a patient with Farber Disease. However, adiponectin overexpression in a Farber Disease mouse model did not improve lifespan or immune infiltration. Intriguingly, mice heterozygous for the Farber Disease mutation were more prone to glucose intolerance and insulin resistance when fed a high-fat diet, and adiponectin overexpression protected from these metabolic perturbations. These studies suggest that adiponectin evokes a ceramidase activity that is not reliant on the functional expression of acid ceramidase, but indicates that additional strategies are required to ameliorate outcomes of Farber Disease

Inducible overexpression of adiponectin receptors highlight the roles of adiponectin-induced ceramidase signaling in lipid and glucose homeostasis

Objective: Adiponectin and the signaling induced by its cognate receptors, AdipoR1 and AdipoR2, have garnered attention for their ability to promote insulin sensitivity and oppose steatosis. Activation of these receptors promotes the deacylation of ceramide, a lipid metabolite that appears to play a causal role in impairing insulin signaling. Methods: Here, we have developed transgenic mice that overexpress AdipoR1 or AdipoR2 under the inducible control of a tetracycline response element. These represent the first inducible genetic models that acutely manipulate adiponectin receptor signaling in adult mouse tissues, which allows us to directly assess AdipoR signaling on glucose and lipid metabolism. Results: Overexpression of either adiponectin receptor isoform in the adipocyte or hepatocyte is sufficient to enhance ceramidase activity, whole body glucose metabolism, and hepatic insulin sensitivity, while opposing hepatic steatosis. Importantly, metabolic improvements fail to occur in an adiponectin knockout background. When challenged with a leptin-deficient genetic model of type 2 diabetes, AdipoR2 expression in adipose or liver is sufficient to reverse hyperglycemia and glucose intolerance. Conclusion: These observations reveal that adiponectin is critical for AdipoR-induced ceramidase activation which enhances hepatic glucose and lipid metabolism via rapidly acting “cross-talk” between liver and adipose tissue sphingolipids. Keywords: Sphingolipid, Insulin resistance, NAFL

Ramadan intermittent fasting is associated with ameliorated inflammatory markers and improved plasma sphingolipids/ceramides in subjects with obesity: lipidomics analysis

Abstract Intermittent fasting (IF) is associated with enormous metabolic alterations that underpin its diverse health effects. Changes in lipid metabolism, particularly ceramides, and other sphingolipids, are among the most notable of these alterations. This study investigated the lipidomic alterations associated with 29–30 days of Ramadan diurnal intermittent fasting (RIF) in metabolically healthy overweight and obese subjects. A prospective cohort of 57 overweight and obese adults (70% males, 38.4 ± 11.2 years), with an age range of 18–58 years was observed prior to and at the conclusion of Ramadan. At both time points, anthropometric, biochemical (lipid profile, glycemic, and inflammatory markers), and dietary intake measurements were taken. Using liquid chromatography-mass spectrometry, a lipidomic analysis of ceramides and other sphingolipids was conducted. Using paired sample t-tests, pre- and post-Ramadan anthropometric, biochemical, and dietary values were compared. RIF was associated with improved levels of lipid profile compartments and inflammatory markers. In addition, RIF was associated with a decrease in plasma sphingosine and sphinganine, which was accompanied by a decrease in sphingosine 1-phosphate and sphinganine 1-phosphate. In addition, RIF was associated with decreased C17, C22, and C24 sphingomyelin, but not C14, C16, C18, C20, and C24:1 sphingomyelin, as well as C20, C22, C24, and C24:1 dihydrosphingomyelin, but not C16 and C18 dihydrosphingomyelin. This study demonstrates that RIF is associated with improvements in plasma sphingosine, sphinganine sphingomyelin, and dihydrosphingomyelin lipid species, as well as improved lipid profile and inflammatory markers, which may confer short-term protection against cardiometabolic problems in patients with overweight/obesity

Phospholipid methylation regulates muscle metabolic rate through Ca2+ transport efficiency

The biophysical environment of membrane phospholipids affects structure, function, and stability of membrane-bound proteins.1,2 Obesity can disrupt membrane lipids, and in particular, alter the activity of sarco/endoplasmic reticulum (ER/SR) Ca2+-ATPase (SERCA) to affect cellular metabolism.3-5 Recent evidence suggests that transport efficiency (Ca2+ uptake / ATP hydrolysis) of skeletal muscle SERCA can be uncoupled to increase energy expenditure and protect mice from diet-induced obesity.6,7 In isolated SR vesicles, membrane phospholipid composition is known to modulate SERCA efficiency.8-11 Here we show that skeletal muscle SR phospholipids can be altered to decrease SERCA efficiency and increase whole-body metabolic rate. The absence of skeletal muscle phosphatidylethanolamine (PE) methyltransferase (PEMT) promotes an increase in skeletal muscle and whole-body metabolic rate to protect mice from diet-induced obesity. The elevation in metabolic rate is caused by a decrease in SERCA Ca2+-transport efficiency, whereas mitochondrial uncoupling is unaffected. Our findings support the hypothesis that skeletal muscle energy efficiency can be reduced to promote protection from obesity

Ceramides Increase Fatty Acid Utilization in Intestinal Progenitors to Enhance Stemness and Increase Tumor Risk

Background & Aims: Cancers of the alimentary tract, including esophageal adenocarcinomas, colorectal cancers, and cancers of the gastric cardia, are common comorbidities of obesity. Prolonged, excessive delivery of macronutrients to the cells lining the gut can increase one's risk for these cancers by inducing imbalances in the rate of intestinal stem cell proliferation vs differentiation, which can produce polyps and other aberrant growths. We investigated whether ceramides, which are sphingolipids that serve as a signal of nutritional excess, alter stem cell behaviors to influence cancer risk. Methods: We profiled sphingolipids and sphingolipid-synthesizing enzymes in human adenomas and tumors. Thereafter, we manipulated expression of sphingolipid-producing enzymes, including serine palmitoyltransferase (SPT), in intestinal progenitors of mice, cultured organoids, and Drosophila to discern whether sphingolipids altered stem cell proliferation and metabolism. Results: SPT, which diverts dietary fatty acids and amino acids into the biosynthetic pathway that produces ceramides and other sphingolipids, is a critical modulator of intestinal stem cell homeostasis. SPT and other enzymes in the sphingolipid biosynthesis pathway are up-regulated in human intestinal adenomas. They produce ceramides, which serve as prostemness signals that stimulate peroxisome-proliferator activated receptor-α and induce fatty acid binding protein-1. These actions lead to increased lipid utilization and enhanced proliferation of intestinal progenitors. Conclusions: Ceramides serve as critical links between dietary macronutrients, epithelial regeneration, and cancer risk