The peptide hormone adropin regulates energy metabolism in skeletal muscle and plays important roles in the regulation of metabolic homeostasis. Besides muscle, the liver has an essential role in regulating glucose homeostasis. Previous studies have reported that treatment of diet-induced obese (DIO) male mice with adropin^34–76 (the putative secreted domain) reduces fasting blood glucose independently of body weight changes, suggesting that adropin suppresses glucose production in the liver. Here, we explored the molecular mechanisms underlying adropin's effects on hepatic glucose metabolism in DIO mice. Male DIO B6 mice maintained on a high-fat diet received five intraperitoneal injections of adropin^34–76 (450 nmol/kg/injection) over a 48-h period. We found that adropin^34–76 enhances major intracellular signaling activities in the liver that are involved in insulin-mediated regulation of glucose homeostasis. Moreover, treatment with adropin^34–76 alleviated endoplasmic reticulum stress responses and reduced activity of c-Jun N-terminal kinase in the liver, explaining the enhanced activities of hepatic insulin signaling pathways observed with adropin^34–76 treatment. Furthermore, adropin^34–76 suppressed cAMP activated protein kinase A (PKA) activities, resulting in reduced phosphorylation of inositol trisphosphate receptor, which mediates endoplasmic reticulum calcium efflux, and of cAMP-responsive element–binding protein, a key transcription factor in hepatic regulation of glucose metabolism. Adropin^34–76 directly affected liver metabolism, decreasing glucose production and reducing PKA-mediated phosphorylation in primary mouse hepatocytes in vitro. Our findings indicate that major hepatic signaling pathways contribute to the improved glycemic control achieved with adropin^34–76 treatment in situations of obesity.

The micropeptide adropin encoded by the clock-controlled Energy homeostasis-associated gene is implicated in the regulation of glucose metabolism. However, its links to rhythms of nutrient intake, energy balance and metabolic control remains poorly defined. Using surveys of Gene Expression Omnibus datasets, we confirm that fasting suppresses liver adropin expression in lean C57L/6J (B6) mice. However, circadian rhythm data are inconsistent. In lean mice, CR induces bouts of compulsive binge feeding separated by prolonged fasting intervals, increasing NAD-dependent deacetylase sirtuin-1 signaling important for glucose and lipid metabolism regulation. CR upregulates adropin expression and induces rhythms correlating with cellular stress-response pathways. Furthermore, adropin expression correlates positively wth phosphoenolpyruvate carboxokinase-1 (Pck1) expression, suggesting a link with gluconeogenesis. Our previous data suggest that adropin suppresses gluconeogenesis in hepatocytes. Liver-specific adropin knockout (LAdrKO) mice exhibit increased glucose excursions following pyruvate injections, indicating increased gluconeogenesis. Gluconeogenesis is also increased in primary cultured hepatocytes derived from LAdrKO mice. Analysis of circulating insulin levels and liver expression of fasting-responsive PKA signaling pathways also suggests enhanced responses in LAdrKO mice during a glucagon tolerance test (250 μg/kg ip.). Fasting-associated changes in PKA signaling are attenuated in transgenic mice constitutively expressing adropin, and in fasting mice treated acutely with adropin peptide. In summary, hepatic adropin expression is regulated by nutrient- and clock-dependent extrahepatic signals. CR induces pronounced post-prandial peaks in hepatic adropin expression. Rhythms of hepatic adropin expression appear to link rhythms in energy balance and cellular stress to the intracellular signal transduction pathways that drive the liver fasting response.

(1) Background: We previously demonstrated that disruption of IP6K1 improves metabolism, protecting mice from high-fat diet-induced obesity, insulin resistance, and non-alcoholic fatty liver disease and steatohepatitis. Age-induced metabolic dysfunction is a major risk factor for metabolic diseases. The involvement of IP6K1 in this process is unknown. (2) Methods: Here, we compared body and fat mass, insulin sensitivity, energy expenditure and serum-, adipose tissue- and liver-metabolic parameters of chow-fed, aged, wild type (aWT) and whole body Ip6k1 knockout (aKO) mice. (3) Results: IP6K1 was upregulated in the adipose tissue and liver of aWT mice compared to young WT mice. Moreover, Ip6k1 deletion blocked age-induced increase in body- and fat-weight and insulin resistance in mice. aKO mice oxidized carbohydrates more efficiently. The knockouts displayed reduced levels of serum insulin, triglycerides, and non-esterified fatty acids. Ip6k1 deletion partly protected age-induced decline of the thermogenic uncoupling protein UCP1 in inguinal white adipose tissue. Targets inhibited by IP6K1 activity such as the insulin sensitivity- and energy expenditure-inducing protein kinases, protein kinase B (PKB/Akt) and AMP-activated protein kinase (AMPK), were activated in the adipose tissue and liver of aKO mice. (4) Conclusions: Ip6k1 deletion maintains healthy metabolism in aging and thus, targeting this kinase may delay the development of age-induced metabolic dysfunction.

In this paper, an improved version of Gravitational Search Algorithm (GSA) called GSA with Wavelet Mutation (GSAWM) is applied for the design of 8th order infinite impulse response (IIR) band pass digital filter. Incorporation of mutation strategy into the conventional GSA technique not only enhances its searching capability but also the chance of convergence to near global solution is increased many folds. Apart from GSA, performance of the proposed optimization technique is compared with some well accepted evolutionary algorithms such as PSO and real coded genetic algorithm (RGA). From the simulation study it can be established that the proposed optimization technique GSAWM outperforms RGA, PSO and GSA, not only in the accuracy of the designed filter but also in terms of convergence speed and solution quality, i.e., the stop band attenuation, transition width, pass band and stop band ripples. Further, the pole-zero analysis justifies the stability of the designed optimized IIR filter.