Hypothalamic orexin prevents non-alcoholic steatohepatitis and hepatocellular carcinoma in obesity.

Non-alcoholic steatohepatitis (NASH) occasionally occurs under obesity; however, factors modulating the natural history of fatty liver disease remain unknown. Since hypothalamic orexin that regulates physical activity and autonomic balance prevents obesity, we investigate its role in NASH development. Male orexin-deficient mice fed a high-fat diet (HFD) show severe obesity and progression of NASH with fibrosis in the liver. Hepatic fibrosis also develops in ovariectomized orexin-deficient females fed an HFD but not ovariectomized wild-type controls. Moreover, long-term HFD feeding causes hepatocellular carcinoma (HCC) in orexin-deficient mice. Intracerebroventricular injection of orexin A or pharmacogenetic activation of orexin neurons acutely activates hepatic mTOR-sXbp1 pathway to prevent endoplasmic reticulum (ER) stress, a NASH-causing factor. Daily supplementation of orexin A attenuates hepatic ER stress and inflammation in orexin-deficient mice fed an HFD, and autonomic ganglionic blocker suppresses the orexin actions. These results suggest that hypothalamic orexin is an essential factor for preventing NASH and associated HCC under obesity.

Hypothalamic orexin prevents hepatic insulin resistance via daily bidirectional regulation of autonomic nervous system in mice.

Circadian rhythm is crucial for preventing hepatic insulin resistance, although the mechanism remains uncovered. Here we report that the wake-active hypothalamic orexin system plays a key role in this regulation. Wild-type mice showed that a daily rhythm in blood glucose levels peaked at the awake period; however, the glucose rhythm disappeared in orexin knockout mice despite normal feeding rhythm. Central administration of orexin A during nighttime awake period acutely elevated blood glucose levels but subsequently lowered daytime glucose levels in normal and diabetic db/db mice. The glucose-elevating and -lowering effects of orexin A were suppressed by adrenergic antagonists and hepatic parasympathectomy, respectively. Moreover, the expression levels of hepatic gluconeogenic genes, including Pepck, were increased and decreased by orexin A at nanomolar and femtomolar doses, respectively. These results indicate that orexin can bidirectionally regulate hepatic gluconeogenesis via control of autonomic balance, leading to generation of the daily blood glucose oscillation. Furthermore, during aging, orexin deficiency enhanced endoplasmic reticulum (ER) stress in the liver and caused impairment of hepatic insulin signaling and abnormal gluconeogenic activity in pyruvate tolerance test. Collectively, the daily glucose rhythm under control of orexin appears to be important for maintaining ER homeostasis, thereby preventing insulin resistance in the liver.

Hypothalamic orexin prevents hepatic insulin resistance induced by social defeat stress in mice.

Depression is associated with insulin resistance and type 2 diabetes, although the molecular mechanism behind the pathological link remains unclear. Orexin, a hypothalamic neuropeptide regulating energy and glucose homeostasis, has been implicated in the endogenous antidepressant mechanism. To clarify whether orexin is involved in the coordination between mental and metabolic functions, we investigated the influence of orexin deficiency on social interaction behavior and glucose metabolism in mice subjected to chronic social defeat stress. Chronic stress-induced glucose intolerance and systemic insulin resistance as well as social avoidance were ameliorated by calorie restriction in an orexin-dependent manner. Moreover, orexin-deficient mice maintained under ad libitum-fed conditions after defeat stress exhibited hyperinsulinemia and elevated HOMA-IR (homeostasis model assessment for insulin resistance), despite normal fasting blood glucose levels. In a pyruvate tolerance test to evaluate hepatic insulin sensitivity, chronic stress-induced abnormal glucose elevation was observed in orexin-deficient but not wild-type mice, although both types of mice were susceptible to chronic stress. In addition, insulin-induced phosphorylation of Akt in the liver was impaired in orexin-deficient but not wild-type mice after chronic stress. These results demonstrate that the central physiological actions of orexin under ad libitum-fed conditions are required for the adaptive response to chronic defeat stress, which can prevent the development of hepatic insulin resistance but not social avoidance behavior. Moreover, calorie restriction, a paradigm to strongly activate orexin neurons, appears to prevent the persistence of depression-like behavior per se, leading to the amelioration of impaired glucose metabolism after chronic stress; therefore, we suggest that hypothalamic orexin system is the key for inhibiting the exacerbating link between depression and type 2 diabetes.

Protective effects of coenzyme Q10 against angiotensin II-induced oxidative stress in human umbilical vein endothelial cells.

Angiotensin II is the major effector in the renin-angiotensin system, and angiotensin II-induced oxidative stress and endothelial dysfunction are profoundly implicated in the pathogenesis of hypertension and cardiovascular disease. In the present study, we investigated the effect of an antioxidant reagent, coenzyme Q10, on angiotensin II-induced oxidative stress in human umbilical vein endothelial cells (HUVEC) to assess its potential usefulness for antioxidant therapy. Treatment of HUVEC with coenzyme Q10 (1-10µM) increased its intracellular levels in a concentration-dependent manner. Coenzyme Q10 (10µM) prevented the actions of angiotensin II (100nM): overproduction of reactive oxygen species, increases in expression of p22(phox) and Nox2 subunits of NADPH oxidase, and inhibition of insulin-induced nitric oxide production. In addition, coenzyme Q10 prevented angiotensin II-induced upregulation of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in HUVEC, and inhibited their adhesion to U937 monocytic cells. Moreover, treatment of HUVEC with coenzyme Q10 effectively ameliorated angiotensin II-induced increases in expression of Nox2 subunit of NADPH oxidase, ICAM-1, and VCAM-1. These results provide the first in vitro evidence that coenzyme Q10 is an efficient antioxidant reagent to improve angiotensin II-induced oxidative stress and endothelial dysfunction, possibly relevant to the causes of cardiovascular disease.