Hypothalamic Orexin Prevents Hepatic Insulin Resistance via Daily Bidirectional Regulation of Autonomic Nervous System in Mice

Abstract

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. Wildtype 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.Maintaining glucose and energy homeostasis throughout the day is essential for survival. Therefore, different metabolic functions are timely activated according to the circadian rhythm. Recently, it has also become clear that fine tuning of daily metabolic rhythms is crucial for preventing metabolic abnormalities. For instance, chronic disruption of circadian rhythm in humans, as seen in shift workers, increases the risk of obesity and type 2 diabetes (1,2), and circadian rhythms of glucose regulation are impaired in diabetic animals and patients with diabetes (3).Circadian rhythms of peripheral tissues, including liver, are entrained to the central biological clock located in the suprachiasmatic nuclei (SCN) via autonomic and hormonal pathways (4). The liver plays a pivotal role in maintaining optimal glucose levels via hepatic glucose production (HGP) and glucose uptake. The daily rhythm of HGP is regulated by the autonomic nervous system under SCN control, leading to generation of a daily rhythm in basal blood glucose levels independently of the feeding rhythm (5). The central clock is also crucial for preventing metabolic abnormalities

Hypothalamic-autonomic control of energy homeostasis

“…Correspondingly, activation of orexin-expressing neurons in the LHA increases blood glucose levels through the stimulation of endogenous glucose production; notably, an intact autonomic outflow via the hepatic sympathetic innervation is essential for this effect [135]. A recent study has shown that knocking out orexin impairs daily rhythm in blood glucose levels [136]. In addition, treatment with an adrenergic antagonist or parasympathectomy suppresses the daynight oscillation of blood glucose levels induced by treatment with OX-A in normal and db/db mice [136].…”

“…A recent study has shown that knocking out orexin impairs daily rhythm in blood glucose levels [136]. In addition, treatment with an adrenergic antagonist or parasympathectomy suppresses the daynight oscillation of blood glucose levels induced by treatment with OX-A in normal and db/db mice [136]. In addition, the VMH has been shown to be involved in hepatic glucose homeostasis.…”

Orexins (hypocretins) and energy balance: More than feeding

“…Accordingly, elevated circulating glucose levels lead to reduced firing of orexin neurons, suggesting that orexins are part of a negative feedback loop, responding to energy status signals (Yamanaka et al, 2003). Recent evidence has also reported that central orexin can bidirectionally regulate hepatic gluconeogenesis, leading to generation of the daily blood glucose oscillation (Tsuneki et al, 2008;Tsuneki et al, 2013;Tsuneki et al, 2015). This mechanism, that is of relevance for circadian regulation of hepatic M A N U S C R I P T…”

“…15 insulin sensitivity, is impaired by aging, when orexin deficiency enhanced endoplasmic reticulum (ER) stress in the liver leading to altered hepatic insulin signaling and abnormal gluconeogenic activity (Tsuneki et al, 2015).…”

Hindbrain Catecholamine Neurons Activate Orexin Neurons During Systemic Glucoprivation in Male Rats

“…Thus, although catecholamine projections to orexin neurons are necessary for orexin activation by glucoprivation, this does not preclude some independent orexin participation in other controls press.endocrine.org/journal/endo 2817 of food intake. A recent study, for example, reports that ablation of orexin neurons using ataxin-3 causes reduced food intake and activity during the dark phase of the circadian cycle, suggesting that an important role for orexin neurons is to coordinate activity state and food seeking based on circadian cues (46). The unusual nonmetabolic glucose-sensing properties of orexin neurons (29, 30) (discussed above) may contribute to their role in circadian control of activity and food intake or other functions of this diverse system of neurons.…”