Junta Imai

Neuronal Pathway from the Liver Modulates Energy Expenditure and Systemic Insulin Sensitivity

Coordinated control of energy metabolism and glucose homeostasis requires communication between organs and tissues. We identified a neuronal pathway that participates in the cross talk between the liver and adipose tissue. By studying a mouse model, we showed that adenovirus-mediated expression of peroxisome proliferator–activated receptor (PPAR)–g2 in the liver induces acute hepatic steatosis while markedly decreasing peripheral adiposity. These changes were accompanied by increased energy expenditure and improved systemic insulin sensitivity. Hepatic vagotomy and selective afferent blockage of the hepatic vagus revealed that the effects on peripheral tissues involve the afferent vagal nerve. Furthermore, an antidiabetic thiazolidinedione, a PPARg agonist, enhanced this pathway. This neuronal pathway from the liver may function to protect against metabolic perturbation induced by excessive energy storage.

Regulation of Pancreatic β Cell Mass by Neuronal Signals from the Liver

Metabolic regulation in mammals requires communication between multiple organs and tissues. The rise in the incidence of obesity and associated metabolic disorders, including type 2 diabetes, has renewed interest in interorgan communication. We used mouse models to explore the mechanism whereby obesity enhances pancreatic β cell mass, pathophysiological compensation for insulin resistance. We found that hepatic activation of extracellular regulated kinase (ERK) signaling induced pancreatic β cell proliferation through a neuronal-mediated relay of metabolic signals. This metabolic relay from the liver to the pancreas is involved in obesity-induced islet expansion. In mouse models of insulin-deficient diabetes, liver-selective activation of ERK signaling increased β cell mass and normalized serum glucose levels. Thus, interorgan metabolic relay systems may serve as valuable targets in regenerative treatments for diabetes.

Impact of Plasma Oxidized Low-Density Lipoprotein Removal on Atherosclerosis

Background— Several clinical studies of statin therapy have demonstrated that lowering low-density lipoprotein (LDL) cholesterol prevents atherosclerotic progression and decreases cardiovascular mortality. In addition, oxidized LDL (oxLDL) is suggested to play roles in the formation and progression of atherosclerosis. However, whether lowering oxLDL alone, rather than total LDL, affects atherogenesis remains unclear. Methods and Results— To clarify the atherogenic impact of oxLDL, lectin-like oxLDL receptor 1 (LOX-1), an oxLDL receptor, was expressed ectopically in the liver with adenovirus administration in apolipoprotein E–deficient mice at 46 weeks of age. Hepatic LOX-1 expression enhanced hepatic oxLDL uptake, indicating functional expression of LOX-1 in the liver. Although plasma total cholesterol, triglyceride, and LDL cholesterol levels were unaffected, plasma oxLDL was markedly and transiently decreased in LOX-1 mice. In controls, atherosclerotic lesions, detected by Oil Red O staining, were markedly increased (by 38%) during the 4-week period after adenoviral administration. In contrast, atherosclerotic progression was almost completely inhibited by hepatic LOX-1 expression. In addition, plasma monocyte chemotactic protein-1 and lipid peroxide levels were decreased, whereas adiponectin was increased, suggesting decreased systemic oxidative stress. Thus, LOX1 expressed in the livers of apolipoprotein E–deficient mice transiently removes oxLDL from circulating blood and possibly decreases systemic oxidative stress, resulting in complete prevention of atherosclerotic progression despite the persistence of severe LDL hypercholesterolemia and hypertriglyceridemia. Conclusions— OxLDL has a major atherogenic impact, and oxLDL removal is a promising therapeutic strategy against atherosclerosis.

Involvement of Apolipoprotein E in Excess Fat Accumulation and Insulin Resistance

Although apolipoprotein E (apoE) is well known to play a major role in lipid metabolism, its role in glucose and energy homeostasis remains unclear. Herein, we established apoE-deficient genetically obese Ay (apoE−/−;Ay/+) mice. ApoE deficiency in Ay mice prevented the development of obesity, with decreased fat accumulation in the liver and adipose tissues. ApoE−/−;Ay/+ mice exhibited better glucose tolerance than apoE+/+;Ay/+ mice. Insulin tolerance testing and hyperinsulinemic-euglycemic clamp study revealed marked improvement of insulin sensitivity, despite increased plasma free fatty acid levels. These metabolic phenotypes were reversed by adenoviral replenishment of apoE protein, indicating circulating apoE to be involved in increased adiposity and obesity-related metabolic disorders. Uptake of apoE-lacking VLDL into the liver and adipocytes was markedly inhibited, but adipocytes in apoE−/−;Ay/+ mice exhibited normal differentiation, suggesting that apoE-dependent VLDL transport is involved in the development of obesity, i.e., surplus fat accumulation. Interestingly, apoE−/−;Ay/+ mice exhibited decreased food intake and increased energy expenditure. Pair-feeding experiments indicate these phenomena to both contribute to the obesity-resistant phenotypes associated with apoE deficiency. Thus, apoE is involved in maintaining energy homeostasis. ApoE-dependent excess fat accumulation is a promising therapeutic target for the metabolic syndrome.

Blockade of the Nuclear Factor-κB Pathway in the Endothelium Prevents Insulin Resistance and Prolongs Life Spans

Background— Nuclear factor-&kgr;B (NF-&kgr;B) signaling plays critical roles in physiological and pathological processes such as responses to inflammation and oxidative stress. Methods and Results— To examine the role of endothelial NF-&kgr;B signaling in vivo, we generated transgenic mice expressing dominant-negative I&kgr;B under the Tie2 promoter/enhancer (E-DNI&kgr;B mice). These mice exhibited functional inhibition of NF-&kgr;B signaling specifically in endothelial cells. Although E-DNI&kgr;B mice displayed no overt phenotypic changes when young and lean, they were protected from the development of insulin resistance associated with obesity, whether diet- or genetics-induced. Obesity-induced macrophage infiltration into adipose tissue and plasma oxidative stress markers were decreased and blood flow and mitochondrial content in muscle and active-phase locomotor activity were increased in E-DNI&kgr;B mice. In addition to inhibition of obesity-related metabolic deteriorations, blockade of endothelial NF-&kgr;B signaling prevented age-related insulin resistance and vascular senescence and, notably, prolonged life span. These antiaging phenotypes were also associated with decreased oxidative stress markers, increased muscle blood flow, enhanced active-phase locomotor activity, and aortic upregulation of mitochondrial sirtuin-related proteins. Conclusions— The endothelium plays important roles in obesity- and age-related disorders through intracellular NF-&kgr;B signaling, thereby ultimately affecting life span. Endothelial NF-&kgr;B signaling is a potential target for treating the metabolic syndrome and for antiaging strategies.

Cold exposure suppresses serum adiponectin levels through sympathetic nerve activation in mice.

Objective: Several lines of evidence suggest important roles for adiponectin in glucose and lipid metabolism and atherosclerosis. However, the mechanisms regulating serum adiponectin levels and adiponectin production are still not completely understood. Our aim was to determine whether adiponectin synthesis is physiologically regulated by the sympathetic nervous system (SNS).

Blockade of the NF-κB Pathway in the Endothelium Prevents Insulin Resistance and Prolongs Lifespans

Background— Nuclear factor-&kgr;B (NF-&kgr;B) signaling plays critical roles in physiological and pathological processes such as responses to inflammation and oxidative stress. Methods and Results— To examine the role of endothelial NF-&kgr;B signaling in vivo, we generated transgenic mice expressing dominant-negative I&kgr;B under the Tie2 promoter/enhancer (E-DNI&kgr;B mice). These mice exhibited functional inhibition of NF-&kgr;B signaling specifically in endothelial cells. Although E-DNI&kgr;B mice displayed no overt phenotypic changes when young and lean, they were protected from the development of insulin resistance associated with obesity, whether diet- or genetics-induced. Obesity-induced macrophage infiltration into adipose tissue and plasma oxidative stress markers were decreased and blood flow and mitochondrial content in muscle and active-phase locomotor activity were increased in E-DNI&kgr;B mice. In addition to inhibition of obesity-related metabolic deteriorations, blockade of endothelial NF-&kgr;B signaling prevented age-related insulin resistance and vascular senescence and, notably, prolonged life span. These antiaging phenotypes were also associated with decreased oxidative stress markers, increased muscle blood flow, enhanced active-phase locomotor activity, and aortic upregulation of mitochondrial sirtuin-related proteins. Conclusions— The endothelium plays important roles in obesity- and age-related disorders through intracellular NF-&kgr;B signaling, thereby ultimately affecting life span. Endothelial NF-&kgr;B signaling is a potential target for treating the metabolic syndrome and for antiaging strategies.

Hepatic glucokinase modulates obesity predisposition by regulating BAT thermogenesis via neural signals.

Considering the explosive increase in obesity worldwide, there must be an unknown mechanism(s) promoting energy accumulation under conditions of overnutrition. We identified a feed-forward mechanism favoring energy storage, originating in hepatic glucokinase (GK) upregulation. High-fat feeding induced hepatic GK upregulation, and hepatic GK overexpression dose-dependently decreased adaptive thermogenesis by downregulating thermogenesis-related genes in brown adipose tissue (BAT). This intertissue (liver-to-BAT) system consists of the afferent vagus from the liver and sympathetic efferents from the medulla and antagonizes anti-obesity effects of leptin on thermogenesis. Furthermore, upregulation of endogenous GK in the liver by high-fat feeding was more marked in obesity-prone than in obesity-resistant strains and was inversely associated with BAT thermogenesis. Hepatic GK overexpression in obesity-resistant mice promoted weight gain, while hepatic GK knockdown in obesity-prone mice attenuated weight gain with increased adaptive thermogenesis. Thus, this intertissue energy-saving system may contribute to determining obesity predisposition.

Interleukin-6 Enhances Glucose-Stimulated Insulin Secretion From Pancreatic β-Cells Potential Involvement of the PLC-IP3–Dependent Pathway

OBJECTIVE Interleukin-6 (IL-6) has a significant impact on glucose metabolism. However, the effects of IL-6 on insulin secretion from pancreatic β-cells are controversial. Therefore, we analyzed IL-6 effects on pancreatic β-cell functions both in vivo and in vitro. RESEARCH DESIGN AND METHODS First, to examine the effects of IL-6 on in vivo insulin secretion, we expressed IL-6 in the livers of mice using the adenoviral gene transfer system. In addition, using both MIN-6 cells, a murine β-cell line, and pancreatic islets isolated from mice, we analyzed the in vitro effects of IL-6 pretreatment on insulin secretion. Furthermore, using pharmacological inhibitors and small interfering RNAs, we studied the intracellular signaling pathway through which IL-6 may affect insulin secretion from MIN-6 cells. RESULTS Hepatic IL-6 expression raised circulating IL-6 and improved glucose tolerance due to enhancement of glucose stimulated-insulin secretion (GSIS). In addition, in both isolated pancreatic islets and MIN-6 cells, 24-h pretreatment with IL-6 significantly enhanced GSIS. Furthermore, pretreatment of MIN-6 cells with phospholipase C (PLC) inhibitors with different mechanisms of action, U-73122 and neomycin, and knockdowns of the IL-6 receptor and PLC-β1, but not with a protein kinase A inhibitor, H-89, inhibited IL-6–induced enhancement of GSIS. An inositol triphosphate (IP3) receptor antagonist, Xestospondin C, also abrogated the GSIS enhancement induced by IL-6. CONCLUSIONS The results obtained from both in vivo and in vitro experiments strongly suggest that IL-6 acts directly on pancreatic β-cells and enhances GSIS. The PLC-IP3–dependent pathway is likely to be involved in IL-6-mediated enhancements of GSIS.

Involvement of Endoplasmic Stress Protein C/EBP Homologous Protein in Arteriosclerosis Acceleration With Augmented Biological Stress Responses

Background— The processes of arteriosclerosis, including atherosclerosis and vascular remodeling, are affected by interactions among numerous biological pathways such as responses to inflammation, oxidative stress, and endoplasmic reticulum stress. C/EBP homologous protein (CHOP), which is well known to induce cellular apoptosis in response to severe endoplasmic reticulum stress, is reportedly upregulated in plaque lesions. Methods and Results— We examined the effects of CHOP deficiency on 2 types of arteriosclerosis: cuff injury–induced neointimal formation and hypercholesterolemia-induced atherosclerosis. Cuff injury–induced neointimal formation was markedly inhibited in CHOP−/− mice with suppressed aortic expression of inflammatory factors and smooth muscle cell proliferation–related proteins. A CHOP deficiency also inhibited aortic plaque formation in hypercholesterolemic apolipoprotein E−/− mice with suppressed aortic expression of inflammatory factors and oxidative stress markers. Bone marrow transplantation experiments revealed that recipient CHOP deficiency significantly suppressed both cuff injury–induced neointimal formation and hypercholesterolemia-induced atherosclerotic plaque formation to a greater extent than donor CHOP deficiency, suggesting the importance of CHOP in vascular cells for arteriosclerosis progression. Furthermore, in our in vitro experiments, in not only macrophages but also endothelial and smooth muscle cell lines, endoplasmic reticulum stress inducers upregulated inflammation-, adhesion-, or smooth muscle cell proliferation–related proteins, whereas decreased CHOP expression remarkably suppressed endoplasmic reticulum stress–induced upregulation of these proteins. Conclusions— In addition to the well-known signaling for apoptosis induction, CHOP may play important roles in augmenting potentially pathological biological stress responses. This noncanonical role of CHOP, especially that expressed in vascular cells, may contribute to the progression of vascular remodeling and atherosclerosis.