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 b1 concomitant with the loss of inositol polyphosphate multikinase (IPMK) in murine myocytes, adipocytes, and hepatocytes. To determine if IPMK was upstream of integrin b1 expression, we examined IPMK 2/2 mouse embryonic fibroblast cells and found that integrins b1 and b3 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 b1 expression, suggesting negative regulation of integrin b1 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.,
SignificanceCigarette smoking is the leading cause of preventable disease and death in the United States. Severe withdrawal symptoms are the reason most people have a hard time quitting smoking. AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis and is activated in response to cellular stressors. We discovered that the AMPK pathway is activated following chronic nicotine use but is repressed following nicotine withdrawal. We reasoned that increasing pAMPK levels pharmacologically might reduce symptoms of nicotine withdrawal. After giving mice metformin, an AMPK activator, we were able to reduce nicotine withdrawal, and found that this was dependent on the presence of the AMPK protein in the hippocampus. This study suggests that AMPK activation could be a target for smoking cessation.
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 insulininduced 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.
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 post-differentiation. Lipid accumulation, lipolysis, β-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 while 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. Conclusion 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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.