No abstract

Type 2 diabetes is a complex disease that is marked by the dysfunction of glucose and lipid metabolism. Hepatic insulin resistance is especially pathogenic in type 2 diabetes, as it dysregulates fasting and postprandial glucose tolerance and promotes systemic dyslipidemia and nonalcoholic fatty liver disease1,2. Mitochondrial dysfunction is closely associated with insulin resistance and might contribute to the progression of diabetes3,4. Here we used previously generated mice5 with hepatic insulin resistance owing to the deletion of the genes encoding insulin receptor substrate-1 (Irs-1) and Irs-2 (referred to here as double-knockout (DKO) mice) to establish the molecular link between dysregulated insulin action and mitochondrial function. The expression of several forkhead box O1 (Foxo1) target genes increased in the DKO liver, including heme oxygenase-1 (Hmox1), which disrupts complex III and IV of the respiratory chain and lowers the NAD+/NADH ratio and ATP production. Although peroxisome proliferator–activated receptor-γ coactivator-1α (Ppargc-1α) was also upregulated in DKO liver, it was acetylated and failed to promote compensatory mitochondrial biogenesis or function. Deletion of hepatic Foxo1 in DKO liver normalized the expression of Hmox1 and the NAD+/NADH ratio, reduced Ppargc-1α acetylation and restored mitochondrial oxidative metabolism and biogenesis. Thus, Foxo1 integrates insulin signaling with mitochondrial function, and inhibition of Foxo1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome.

Insulin controls nutrient and metabolic homeostasis via the IRS–PI3K–AKT signaling cascade that targets FOXO1 and mTOR. Mitochondria, as the prime metabolic platform, malfunction during insulin resistance in metabolic diseases. However, the molecular link between insulin resistance and mitochondrial dysfunction remains undefined. Here we review recent studies on insulin action and the mechanistic association with mitochondrial metabolism. These studies suggest that insulin signaling underpins mitochondrial electron transport chain integrity and activity by suppressing FOXO1/HMOX1 and maintaining the NAD+/NADH ratio, the mediator of the SIRT1/PGC1α pathway for mitochondrial biogenesis and function. Mitochondria generate moderately reactive oxygen species (ROS) and enhance insulin sensitivity upon redox regulation of protein tyrosine phosphatase and insulin receptor. However, chronic exposure to high ROS levels could alter mitochondrial function and thereby cause insulin resistance.

Aerogels derived from nanocellulose have emerged as attractive absorbents for cleaning up oil spills and organic pollutants due to their lightweight, exceptional absorption capacity, and sustainability. However, the majority of the nanocellulose aerogels based on the bottom-up fabrication process still lack sufficient mechanical robustness because of their disordered architecture with randomly assembled cellulose nanofibrils, which is an obstacle to their practical application as oil absorbents. Herein, we report an effective strategy to create anisotropic cellulose-based wood sponges with a special spring-like lamellar structure directly from natural balsa wood. The selective removal of lignin and hemicelluloses via chemical treatment broke the thin cell walls of natural wood, leading to a lamellar structure with wave-like stacked layers upon freeze-drying. A subsequent silylation reaction allowed the growth of polysiloxane coatings on the skeleton surface. The resulting silylated wood sponge exhibited high mechanical compressibility (reversible compression of 60%) and elastic recovery (∼99% height retention after 100 cycles at 40% strain). The wood sponge showed excellent oil/water absorption selectivity with a high oil absorption capacity of 41 g g–1. Moreover, the absorbed oils can be recovered by simple mechanical squeezing, and the porous sponge maintained a high oil-absorption capacity upon multiple squeezing-absorption cycles, displaying excellent recyclability. Taking advantage of the unidirectional liquid transport of the porous sponge, an oil-collecting device was successfully designed to continuously separate contaminants from water. Such an easy, low-cost, and scalable top-down approach holds great potential for developing effective and reusable oil absorbents for oil/water separation.

Forkhead box O (FOXO) transcription factors have been implicated in regulating the metabolism, cellular proliferation, stress resistance, apoptosis, and longevity. Through the insulin receptor substrate ? phosphoinositide 3-kinase ? Akt signal cascade, FOXO integrates insulin action with the systemic nutrient and energy homeostasis. Activation of FOXO1 in liver induces gluconeogenesis via phosphoenolpyruvate carboxykinase (PEPCK)=glucose 6-phosphate pathway, and disrupts mitochondrial metabolism and lipid metabolism via heme oxygenase 1=sirtuin 1=Ppargc1a pathway. In skeletal muscle, FOXO1 activation underpins the carbohydrate=lipid switch during fasting state. Inhibition of FOXO1 under physiological conditions accounts for maintenance of skeletal muscle mass=function and adipose differentiation. In pancreatic b-cells, nuclear translocation of FOXO1 antagonizes pancreatic and duodenal homeobox 1 and attenuates b-cells proliferation and insulin secretion. Regardless, FOXO1 promotes the proliferation of b-cells through induction of Cyclin D1 in low nutrition, and elicits antioxidant mechanism to protect against b-cell failure during oxidative insults. In the brain, FOXO1 controls food intake through transcriptional regulation of the orexigenic neuropeptide Y, agouti-related protein, and carboxypeptidase E. In this article, we review the role of FOXO1 in the regulation of metabolism and energy expenditure based on recent findings from mouse models, and discuss the therapeutic value of targeting FOXO1 in metabolic diseases. Antioxid. Redox Signal. 14, 649-661.

We used a Cre-loxP approach to generate mice with varied expression of hepatic Irs1 and Irs2 to establish the contribution of each protein to hepatic nutrient homeostasis. While nutrient-sensitive transcripts were expressed nearly normally in liver lacking Irs2 (LKO2 mice), these transcripts were significantly dysregulated in liver lacking Irs1 (LKO1 mice) or Irs1 and Irs2 together (DKO mice). Similarly, a set of key gluconeogenic and lipogenic genes was regulated nearly normally by feeding in liver retaining a single Irs1 allele without Irs2 (DKO/1 mice) but was poorly regulated in liver retaining one Irs2 allele without Irs1 (DKO/2 mice). DKO/2 mice, but not DKO/1 mice, also showed impaired glucose tolerance and insulin sensitivity-though both Irs1 and Irs2 were required to suppress hepatic glucose production during hyperinsulinemic-euglycemic clamp. In contrast, either hepatic Irs1 or Irs2 mediated suppression of HGP by intracerebroventricular insulin infusion. After 12 weeks on a high-fat diet, postprandial tyrosine phosphorylation of Irs1 increased in livers of control and LKO2 mice, whereas tyrosine phosphorylation of Irs2 decreased in control and LKO1 mice. Moreover, LKO1 mice-but not LKO2 mice-that were fed a high-fat diet developed postprandial hyperglycemia. We conclude that Irs1 is the principal mediator of hepatic insulin action that maintains glucose homeostasis.

Coordination of skeletal muscle growth and metabolism with nutrient availability is critical for metabolic homeostasis. To establish the role of insulin-like signaling in this process, we used muscle creatine kinase (MCK)-Cre to disrupt expression of insulin receptor substrates Irs1 and Irs2 in mouse skeletal/cardiac muscle. In 2-week-old mice, skeletal muscle masses and insulin responses were slightly affected by Irs1, but not Irs2, deficiency. In contrast, the combined deficiency of Irs1 and Irs2 (MDKO mice) severely reduced skeletal muscle growth and Akt3mTOR signaling and caused death by 3 weeks of age. Autopsy of MDKO mice revealed dilated cardiomyopathy, reflecting the known requirement of insulin-like signaling for cardiac function (P. G. Laustsen et al., Mol. Cell. Biol. 27:1649-1664, 2007). Impaired growth and function of MDKO skeletal muscle were accompanied by increased Foxo-dependent atrogene expression and amino acid release. MDKO mice were resistant to injected insulin, and their isolated skeletal muscles showed decreased insulin-stimulated glucose uptake. Glucose utilization in MDKO mice and isolated skeletal muscles was shifted from oxidation to lactate production, accompanied by an elevated AMP/ATP ratio that increased AMP-activated protein kinase (AMPK)3acetyl coenzyme A carboxylase (ACC) phosphorylation and fatty acid oxidation. Thus, insulin-like signaling via Irs1/2 is essential to terminate skeletal muscle catabolic/fasting pathways in the presence of adequate nutrition.

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