Adipose tissue stores triacylglycerol (TAG) in lipid droplets (LD) and release fatty acids upon lipolysis during energy shortage. We identify ApoL6 as a LD-associated protein mainly found in adipose tissue, specifically in adipocytes. ApoL6 expression is low during fasting but induced upon feeding. ApoL6 knockdown results in smaller LD with lower TAG content in adipocytes, while ApoL6 overexpression causes larger LD with higher TAG content. We show that the ApoL6 affects adipocytes through inhibition of lipolysis. While ApoL6, Perilipin 1 (Plin1), and HSL can form a complex on LD, C-terminal ApoL6 directly interacts with N-terminal Plin1 to prevent Plin1 binding to HSL, to inhibit lipolysis. Thus, ApoL6 ablation decreases white adipose tissue mass, protecting mice from diet-induced obesity, while ApoL6 overexpression in adipose brings obesity and insulin resistance, making ApoL6 a potential future target against obesity and diabetes.

Acylglycerophosphate acyltransferase 4 (AGPAT4)/lysophosphatidic acid acyltransferase delta catalyzes the formation of phosphatidic acid (PA), a precursor of triacyl­glycerol (TAG). We investigated the effect of Agpat4 gene ablation on white adipose tissue (WAT) after finding consistent expression across depots. Epididymal WAT mass was 40% larger in male Agpat4^−/− mice than wild-type littermates, but unchanged in perirenal, retroperitoneal, and inguinal WAT and subscapular brown adipose tissue. Metabolic changes were identified in epididymal WAT that were not evident in perirenal WAT, which was analyzed for comparison. The total epididymal TAG content doubled, increasing adipocyte cell size without changing markers of differentiation. Enzymes involved in de novo lipogenesis and complex lipid synthesis downstream of phosphatidic acid production were also unchanged. However, total epididymal TAG hydrolase activity was reduced, and there were significant decreases in total ATGL and reduced phosphorylation of hormone-sensitive lipase at the S563 and S660 PKA-activation sites. Analysis of Agpats 1, 2, 3, and 5, as well as Gpats 1, 2, 3, and 4, demonstrated compensatory upregulation in perirenal WAT that did not occur in epididymal WAT. Our findings therefore indicate depot-specific differences in the redundancy of Agpat4 and highlight the molecular and metabolic heterogeneity of individual visceral depots.

We previously characterized LPAATδ/AGPAT4 as a mitochondrial lysophosphatidic acid acyltransferase that regulates brain levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI). Here we report that Lpaatδ ^-/- mice display impaired spatial learning and memory compared to wildtype littermates in the Morris Water Maze, and investigated potential mechanisms associated with brain phospholipid changes. Marker protein immunoblotting suggested that the relative brain content of neurons, glia, and oligodendrocytes was unchanged. Relative abundance of the important brain fatty acid docosahexaenoic acid was also unchanged in phosphatidylserine, phosphatidylglycerol, and cardiolipin, in agreement with prior data on PC, PE and PI. In phosphatidic acid, it was increased. Specific decreases in ethanolamine-containing phospholipids were detected in mitochondrial lipids, but the function of brain mitochondria in Lpaatδ^-/- mice was unchanged. Importantly, we found that Lpaatδ^-/- mice have a significantly and drastically lower brain content of the NMDA receptor subunits NR1, NR2A and NR2B, as well as the AMPA receptor subunit GluR1, compared to wildtype mice. However, general dysregulation of PI-mediated signaling is not likely responsible, since phospho-AKT and phospho-mTOR pathway regulation was unaffected. Our findings indicate that Lpaatδ deficiency causes deficits in learning and memory associated with reduced NMDA and AMPA receptors.