Search

The AHNAK nucleoprotein has been determined to exert an anti-obesity effect in adipose tissue and further inhibit adipogenic differentiation. In this study, we examined the role of AHNAK in regulating hepatic lipid metabolism to prevent diet-induced fatty liver. Ahnak KO mice have reportedly exhibited reduced fat accumulation in the liver and decreased serum triglyceride (TG) levels when provided with either a normal chow diet or a high-fat diet (HFD). Gene expression profiling was used to identify novel factors that could be modulated by genetic manipulation of the Ahnak gene. The results revealed that fibroblast growth factor 21 (FGF21) was markedly increased in the livers of Ahnak KO mice compared with WT mice fed a HFD. Ahnak knockdown in hepatocytes reportedly prevented excessive lipid accumulation induced by palmitate treatment and was associated with increased secretion of FGF21 and the expression of genes involved in fatty acid oxidation, which are primarily downstream of PPARα. These results indicate that pronounced obesity and hepatic steatosis are attenuated in HFD-fed Ahnak KO mice. This may be attributed, in part, to the induction of FGF21 and regulation of lipid metabolism, which are considered to be involved in increased fatty acid oxidation and reduced lipogenesis in the liver. These findings suggest that targeting AHNAK may have beneficial implications in preventing or treating hepatic steatosis., Liver disease: A potential treatment for nonalcoholic fatty liver A protein that modulates lipid accumulation could be a target for controlling nonalcoholic fatty liver disease (NAFLD). The AHNAK protein regulates fat cell development, and mice lacking AHNAK are less susceptible to obesity after being fed a HFD. South Korean researchers led by Je Kyung Seong of Seoul National University and Yun Soo Bae of Ewha Womans University, Seoul, have identified a mechanism by which AHNAK inhibition prevents lipid accumulation in NAFLD. The authors profiled gene expression in AHNAK-deficient mice, and noted a striking increase in levels of a signaling protein called FGF21 in the liver. This elevated FGF21 was in turn linked to increased breakdown and reduced production of fatty acids. Therapeutic interventions that inhibit AHNAK could help control NAFLD, a hard-to-treat condition that can ultimately lead to cirrhosis and liver failure.

Hes6 is a member of the hairy-enhancer of split homolog (Hes) family of transcription factors and interacts with other Hes family genes. During development, Hes genes are expressed in neural stem cells and progenitor cells. However, the role of Hes6 in adult hippocampal neurogenesis remains unclear. We therefore investigated the effects of Hes6 on adult hippocampal neurogenesis, by comparing Hes6 knockout and wild-type mice. To this end, we immunostained for markers of neural stem cells and progenitor cells (nestin), proliferating cells (Ki67), post-mitotic neuroblasts and immature neurons (doublecortin, DCX), mature neuronal cells (NeuN), and astrocyte (S100β). We also injected 5-bromo-2'-deoxyuridine (BrdU) to trace the fate of mitotic cells. Nestin- and Ki67-positive proliferating cells did now show any significant differences between wild and knockout groups. Hes6 knockout negatively affects neuroblast differentiation based on DCX immunohistochemistry. On the contrary, the ratio of the BrdU and NeuN double-positive cells did not show any significance, even though it was slightly higher in the knockout group. These results suggest that Hes6 is involved in the regulation of neuroblast differentiation during adult neurogenesis, but does not influence integration into mature neurons.

In adipose tissue, agonists of the β3-adrenergic receptor (ADRB3) regulate lipolysis, lipid oxidation, and thermogenesis. The deficiency in the thermogenesis induced by neuroblast differentiation-associated protein AHNAK in white adipose tissue (WAT) of mice fed a high-fat diet suggests that AHNAK may stimulate energy expenditure via development of beige fat. Here, we report that AHNAK deficiency promoted browning and thermogenic gene expression in WAT but not in brown adipose tissue of mice stimulated with the ADRB3 agonist CL-316243. Consistent with the increased thermogenesis, Ahnak−/− mice exhibited an increase in energy expenditure, accompanied by elevated mitochondrial biogenesis in WAT depots in response to CL-316243. Additionally, AHNAK-deficient WAT contained more eosinophils and higher levels of type 2 cytokines (IL-4/IL-13) to promote browning of WAT in response to CL-316243. This was associated with enhanced sympathetic tone in the WAT via upregulation of adrb3 and tyrosine hydroxylase (TH) in response to β-adrenergic activation. CL-316243 activated PKA signalling and enhanced lipolysis, as evidenced by increased phosphorylation of hormone-sensitive lipase and release of free glycerol in Ahnak−/− mice compared to wild-type mice. Overall, these findings suggest an important role of AHNAK in the regulation of thermogenesis and lipolysis in WAT via β-adrenergic signalling.