IPMK modulates hepatic glucose production and insulin signaling.

Hepatic glucose production (HGP) is crucial for the maintenance of normal glucose homeostasis. Although hepatic insulin resistance contributes to excessive glucose production, its mechanism is not well understood. Here, we show that inositol polyphosphate multikinase (IPMK), a key enzyme in inositol polyphosphate biosynthesis, plays a role in regulating hepatic insulin signaling and gluconeogenesis both in vitro and in vivo. IPMK-deficient hepatocytes exhibit decreased insulin-induced activation of Akt-FoxO1 signaling. The expression of messenger RNA levels of phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose 6-phosphatase (G6pc), key enzymes mediating gluconeogenesis, are increased in IPMK-deficient hepatocytes compared to wild type hepatocytes. Importantly, re-expressing IPMK restores insulin sensitivity and alleviates glucose production in IPMK-deficient hepatocytes. Moreover, hepatocyte-specific IPMK deletion exacerbates hyperglycemia and insulin sensitivity in mice fed a high-fat diet, accompanied by an increase in HGP during pyruvate tolerance test and reduction in Akt phosphorylation in IPMK deficient liver. Our results demonstrate that IPMK mediates insulin signaling and gluconeogenesis and may be potentially targeted for treatment of diabetes.

Dolutegravir Suppresses Thermogenesis via Disrupting Uncoupling Protein 1 Expression and Mitochondrial Function in Brown/Beige Adipocytes in Preclinical Models.

BACKGROUND: Antiretroviral therapy (ART) containing integrase strand transfer inhibitors (INSTIs) has been associated with weight gain in both ART initiation and switch studies, especially in women, but the underlying mechanisms are unclear. METHODS: The effects of dolutegravir (DTG) on food intake, energy expenditure, oxygen consumption in female mice, and gene expression from adipose tissues were assessed. Human and murine preadipocytes were treated with DTG either during differentiation into mature brown/beige adipocytes or postdifferentiation. Lipid accumulation, lipolysis, ß-adrenergic response, adipogenic markers, mitochondrial respiration, and insulin response were analyzed. RESULTS: Two-week administration of DTG to female mice reduced energy expenditure, which was accompanied by decreased uncoupling protein 1 (UCP1) expression in brown/beige adipose tissues. In vitro studies showed that DTG significantly reduced brown adipogenic markers, especially UCP1 in brown and beige adipocytes, whereas drugs from other classes did not. Furthermore, a loss of UCP1 by DTG led to a decrease in mitochondrial complex IV component, followed by a reduction in mitochondrial respiratory capacity and reduced insulin-stimulated glucose uptake. CONCLUSIONS: Our findings show that DTG targets UCP1 and mitochondrial functions in brown and beige adipocytes and disrupts thermogenic functions in preclinical models, providing the potential mechanisms by which DTG suppresses energy expenditure leading to weight gain.

Inositol polyphosphate multikinase is a metformin target that regulates cell migration.

Metformin has been shown to alter cell adhesion protein expression, which is thought to play a role in its observed antitumor properties. We found that metformin treatment down-regulated integrin ß1 concomitant with the loss of inositol polyphosphate multikinase (IPMK) in murine myocytes, adipocytes, and hepatocytes. To determine if IPMK was upstream of integrin ß1 expression, we examined IPMK-/- mouse embryonic fibroblast cells and found that integrins ß1 and ß3 gene expression was reduced by half, relative to wild-type cells, whereas focal adhesion kinase (FAK) activity and Rho/Rac/Cdc42 protein levels were increased, resulting in migration defects. Using nanonet force microscopy, we determined that cell:extracellular matrix adhesion and cell contractility forces were decreased, confirming the functional relevance of integrin and Rho protein dysregulation. Pharmacological studies showed that inhibition of both FAK1 and proline-rich tyrosine kinase 2 partially restored integrin ß1 expression, suggesting negative regulation of integrin ß1 by FAK. Together our data indicate that IPMK participates in the regulation of cell migration and provides a potential link between metformin and wound healing impairment.-Tu-Sekine, B., Padhi, A., Jin, S., Kalyan, S., Singh, K., Apperson, M., Kapania, R., Hur, S. C., Nain, A., Kim, S. F. Inositol polyphosphate multikinase is a metformin target that regulates cell migration.

Activation of AMPK by metformin improves withdrawal signs precipitated by nicotine withdrawal.

Cigarette smoking is the leading cause of preventable disease and death in the United States, with more persons dying from nicotine addiction than any other preventable cause of death. Even though smoking cessation incurs multiple health benefits, the abstinence rate remains low with current medications. Here we show that the AMP-activated protein kinase (AMPK) pathway in the hippocampus is activated following chronic nicotine use, an effect that is rapidly reversed by nicotine withdrawal. Increasing pAMPK levels and, consequently, downstream AMPK signaling pharmacologically attenuate anxiety-like behavior following nicotine withdrawal. We show that metformin, a known AMPK activator in the periphery, reduces withdrawal symptoms through a mechanism dependent on the presence of the AMPKα subunits within the hippocampus. This study provides evidence of a direct effect of AMPK modulation on nicotine withdrawal symptoms and suggests central AMPK activation as a therapeutic target for smoking cessation.