Dysregulation of the pathways involved in adipogenesis, lipid metabolism, and energy homeostasis can lead to the development of obesity, hepatic steatosis, diabetes, and dyslipidemia. Here, we present novel evidence that TDAG51 plays a significant role in the regulation of energy and lipid metabolism. First, the findings of this study show for the first time that TDAG51 is expressed in WAT and that its protein expression is modulated during adipogenesis. Given that TDAG51 protein expression is minimal or absent in mature mouse and human adipocytes, TDAG51 may be a useful preadipocyte marker. Second, deletion of TDAG51 enhances lipid accumulation during adipogenesis and accelerates fatty acid/TG synthesis in primary hepatocytes. Third, the absence of TDAG51 leads to an age-associated increase in whole-body adiposity and hepatic TG accumulation, and decreases metabolic rate and insulin sensitivity in standard chow diet–fed WT mice. Notably, the phenotype observed in TDAG51−/− mice resembles several aspects of high-fat diet–fed WT mice. Finally, TDAG51 protein expression is inversely correlated with hepatic steatosis.
The age-dependent increase in adiposity, hepatic TG accumulation, and systemic IR in TDAG51−/−
mice are suggestive of a chronic and cumulative effect, likely attributable to a decrease in metabolic rate and increased lipogenesis. Excessive accumulation of TG can culminate in the expansion of WAT, ectopic lipid accumulation, and eventually IR in combination with chronic inflammation and oxidative stress (35
), which is consistent with the phenotype observed in older TDAG51−/−
mice. Moreover, when cells become insulin resistant, not all pathways are blunted as lipogenic pathways remain active, a concept known as selective IR (37
). The reduced Akt phosphorylation in combination with increased SREBP-1 activation seen in livers from insulin-injected TDAG51−/−
mice is consistent with selective IR. The absence of TDAG51 in mice culminated in increased TG deposition in the liver. Numerous studies show a strong correlation between fatty liver and whole-body IR (38
), suggesting that increased hepatic steatosis and selective IR in the liver of TDAG51−/−
mice may be contributing to the systemic IR phenotype in these mice. Given that SREBP-1 is a master regulator of hepatic de novo lipogenesis (32
) and an increase in SREBP-1 target gene expression was observed in TDAG51−/−
livers, the absence of TDAG51 likely leads to hepatic steatosis through increased SREBP-1 activity. Consistent with this result, primary TDAG51−/−
hepatocytes exhibited a significant enhancement in the rate of lipogenesis, which correlates with the strong association between TDAG51 reduction and fatty livers. Taken together, these data suggest a role for TDAG51 in the negative regulation of SREBP-mediated lipogenesis and prevention of fatty liver.
TDAG51 has several important domains, including a PH-like domain, which appears to be a likely candidate for functional significance in the context of cell signaling and metabolism. For instance, a recent study identified a novel PH domain–containing protein involved in the regulation of adipocyte insulin signaling (43
). Indeed, TDAG51 was identified as a specific IGF-1 target gene in NIH-3T3 fibroblasts and was shown to mediate the effects of IGF-1 on cell survival (44
). Furthermore, previous studies suggest that extracellular signal–related kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) signaling can modulate TDAG51 expression (44
). However, the exact cellular mechanisms by which IGF-1, ERK, or p38 MAPK induces TDAG51 expression are unknown.
PH domains play an important role in recruiting target proteins to cell membranes through their binding interactions with phospholipids such as phosphatidylinositol (3-5)-triphosphate (PIP3) and phosphatidylinositol (4,5)-bisphosphate (PIP2) (46
). Interestingly, TDAG51 has a high stringency PIP3-binding site in its PH-like domain, as predicted by ScanSite (48
). Furthermore, the PH-like domain of TDAG51 exhibits a high degree of homology to that of phosphatidylinositol 3-kinase (PI3K) enhancer (PIKE), as predicted by the Protein Homology/Analog Y Recognition Engine (Phyre2) (49
). Interestingly, PIKE has recently been implicated in playing a role in adipogenesis, WAT regulation, and insulin sensitivity, and in contrast to TDAG51−/−
mice are protected from diet-induced weight gain and IR (50
). Thus, we are currently exploring whether the PH-like domain of TDAG51 is indeed mediating its effects on the regulation of lipogenesis and whole-body energy metabolism and whether the PI3K/Akt pathway may be involved.
Collectively, the results of our study illustrate that TDAG51 plays an important role as a regulator of carbohydrate and lipid metabolism, at least in part through regulating SREBP activity, which may contribute to the phenotypes observed with the metabolic syndrome. Understanding this newly identified cellular factor in lipid metabolism and adipogenesis as well as its precise regulation under normal and pathophysiological conditions will be crucial for the development of effective treatments against diabetes and obesity.