Emerging evidence suggests that impaired regulation of adipocyte lipolysis contributes to the proinflammatory immune cell infiltration of metabolic tissues in obesity, a process that is proposed to contribute to the development and exacerbation of insulin resistance. To test this hypothesis in vivo, we generated mice with adipocyte-specific deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme catalyzing triacylglycerol hydrolysis. In contrast to previous models, adiponectin-driven Cre expression was used for targeted ATGL deletion. The resulting adipocyte-specific ATGL knockout (AAKO) mice were then characterized for metabolic and immune phenotypes. Lean and diet-induced obese AAKO mice had reduced adipocyte lipolysis, serum lipids, systemic lipid oxidation, and expression of peroxisome proliferator-activated receptor alpha target genes in adipose tissue (AT) and liver. These changes did not increase overall body weight or fat mass in AAKO mice by 24 weeks of age, in part due to reduced expression of genes involved in lipid uptake, synthesis, and adipogenesis. Systemic glucose and insulin tolerance were improved in AAKO mice, primarily due to enhanced hepatic insulin signaling, which was accompanied by marked reduction in diet-induced hepatic steatosis as well as hepatic immune cell infiltration and activation. In contrast, although adipocyte ATGL deletion reduced AT immune cell infiltration in response to an acute lipolytic stimulus, it was not sufficient to ameliorate, and may even exacerbate, chronic inflammatory changes that occur in AT in response to diet-induced obesity.
Background: Ypk1 is a protein kinase known to regulate sphingolipid homeostasis. Plb1 deacylates phosphatidylcholine to produce glycerophosphocholine. Results: Loss of Ypk1 or disruption of sphingolipid synthesis by other means elevates Plb1-mediated phosphatidylcholine turnover. Conclusion: Accelerated turnover of phosphatidylcholine compensates for aberrant sphingolipid synthesis. Significance: Sphingolipid synthesis is coordinated with phosphatidylcholine metabolism to maintain membrane lipid homeostasis.
Saccharomyces cerevisiae produces extracellular glycerophosphoinositol through phospholipase-mediated turnover of phosphatidylinositol and transports glycerophosphoinositol into the cell upon nutrient limitation. A screening identified the RAS GTPase-activating proteins Ira1 and Ira2 as required for utilization of glycerophosphoinositol as the sole phosphate source, but the RAS/cyclic AMP pathway does not appear to be involved in the growth phenotype. Ira1 and Ira2 affect both the production and transport of glycerophosphoinositol.
Ypk1, the yeast homolog of the human serum‐ and glucocorticoid‐induced kinase (Sgk1), is a serine/threonine protein kinase known to affect various downstream processes, including plasma membrane flippase activity and sphingolipid homeostasis. The results described here indicate that Ypk1 also impinges upon the turnover of phospholipids. Pulse‐chase experiments reveal that a ypk1 mutant exhibits alterations in phospholipid deacylation and resultant glycerophosphodiester production as compared to a wild type strain. Furthermore, loss of Plb1, a plasma membrane (PM) associated phospholipase, in a ypk1 background results in further alterations in phospholipid deacylation and a growth defect. We are in the process of examining potential explanations for the altered Plb1 activity in the ypk1 mutant. Strains in which other phospholipase B‐encoding genes are deleted in combination with YPK1 do not display a growth defect, suggesting a specific functional interaction between Plb1 and Ypk1. Preliminary studies have identified model PM proteins, including the Git1 permease, whose activity is affected by loss of Ypk1 and/or Plb1. Our data is consistent with the idea that Ypk1 and Plb1 alter plasma membrane phospholipid composition, which in turn impinges upon the activity of integral plasma membrane proteins.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.