Morphological evidence for neural interactions between leptin and orexin in the hypothalamus

Funahashi, Hiroomi; Hori, Toshiko; Shimoda, Yoshimi; Mizushima, Hidekatsu; Ryushi, Tomoo; Katoh, Sachi; Shioda, Seiji

doi:10.1016/s0167-0115(00)00146-4

Cited by 55 publications

(30 citation statements)

References 34 publications

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“…Both contain glucosensing neurons that respond to differing levels of glucose and are linked to pathways involved in the regulation of glucose homeostasis (3)(4)(5)(6)(7)(8)(9)(10)(11) and the counterregulatory responses to hypoglycemia (12)(13)(14)(15)(16)(17)(18)(19). Our work (6,7) and that of others (8) strongly support a role for glucokinase (hexokinase IV) as a key regulator of neuronal glucosensing, which is similar to its purported role in pancreatic ␤-cell glucosensing (20,21).…”

supporting

confidence: 67%

Glucokinase Is a Critical Regulator of Ventromedial Hypothalamic Neuronal Glucosensing

et al. 2006

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To test the hypothesis that glucokinase is a critical regulator of neuronal glucosensing, glucokinase activity was increased, using a glucokinase activator drug, or decreased, using RNA interference combined with calcium imaging in freshly dissociated ventromedial hypothalamic nucleus (VMN) neurons or primary ventromedial hypothalamus (VMH; VMN plus arcuate nucleus) cultures. To assess the validity of our approach, we first showed that glucoseinduced (0.5-2.5 mmol/l) changes in intracellular Ca U nlike most neurons in the brain that utilize glucose to fuel their metabolic needs (1), a select group of neurons use glucose as a signaling molecule to alter their firing rate as a means of glucosensing (2,3). Glucose-excited neurons increase, whereas glucose-inhibited neurons decrease, their firing rate as ambient glucose levels rise (2-7). During situations of low glucose availability, glucose-inhibited neurons are activated and glucose-excited neurons inactivated (4 -8).The ventromedial hypothalamus (VMH) area contains both the ventromedial hypothalamic nucleus (VMN) and arcuate nucleus. Both contain glucosensing neurons that respond to differing levels of glucose and are linked to pathways involved in the regulation of glucose homeostasis (3-11) and the counterregulatory responses to hypoglycemia (12-19). Our work (6,7) and that of others (8) strongly support a role for glucokinase (hexokinase IV) as a key regulator of neuronal glucosensing, which is similar to its purported role in pancreatic ␤-cell glucosensing (20,21). We previously demonstrated that inhibition of glucokinase activity reduced glucose-excited and increased glucose-inhibited neuronal activity at 2.5 mmol/l glucose, the concentration at which they are normally active and inactive, respectively (6,7).Recurrent hypoglycemia is common in patients with type 1 diabetes, especially in children (22)(23)(24)(25). This leads to hypoglycemia-associated autonomic failure, in which counterregulatory responses to subsequent bouts of hypoglycemia are severely blunted (26 -28). Our previous studies suggested that the development of hypoglycemiaassociated autonomic failure might be associated with changes in the ability of VMH neurons to sense and respond to glucose (6,28). Furthermore, its development is associated with upregulation of glucokinase mRNA in the VMH (6,28,29). This upregulation might be a compensatory response that makes glucosensing neurons more sensitive to glucose by shifting their concentration-response to the left. If so, this could underlie the development of hypoglycemia-associated autonomic failure because it would require lower levels of glucose to be reached before counterregulatory responses were initiated. This would predict that increasing glucokinase activity would produce a leftward shift in glucose sensitivity in VMH glucosensing neurons such as it does in pancreatic ␤-cells, using a drug that increases glucokinase activity (30). It would also predict that reducing glucokinase activity would inhibit the response to glucose. Here, we ...

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confidence: 67%

Glucokinase Is a Critical Regulator of Ventromedial Hypothalamic Neuronal Glucosensing

et al. 2006

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“…If fat intake alters NMU sensitivity in the PVN, another factor must account for the differential susceptibility of DIO and DR rats. Second, the decreased sensitivity to peptides such as NMU or orexin could be secondary to the obesity and the concomitant effects on adiposity seen in the DIO rats both in this study and elsewhere [59], including changes in circulating hormones [16,64,99] and other physiological sequalae of obesity. Conditions of positive or negative energy balance can change brain NMU expression [19,29,34].…”

Section: Discussionmentioning

confidence: 85%

Sensitivity of the hypothalamic paraventricular nucleus to the locomotor-activating effects of neuromedin U in obesity

2007

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Obesity is associated with a decrease in energy expenditure relative to energy intake. The decrease in physical activity associated with obesity in several species, including humans, contributes to decreased energy expenditure. Several hormones and neuropeptides that affect appetite also modulate physical activity, including neuromedin U (NMU), a peptide found in the gut and brain. We have demonstrated that NMU microinjected into the hypothalamic paraventricular nucleus (PVN) in rats increases the energy expenditure associated with physical activity, called non-exercise activity thermogenesis (NEAT). Here we examined whether obesity in rats is related to decreased sensitivity of the PVN to the locomotor-activating effect of NMU. Diet-induced obese (DIO) rats and lean, dietresistant (DR) rats were given PVN microinjections of increasing doses of NMU both before and after one month on a high-fat diet. We found that NMU increases physical activity, energy expenditure, and NEAT in a dose-dependent manner in both DR and DIO rats, both before and after one month on the high-fat diet. Before high-fat feeding, the obesity-prone and lean rats showed similar levels of physical activity after intra-PVN microinjections of NMU. After one month of the high-fat diet, however, the obesity-resistant rats showed significantly more NMU-induced physical activity compared to the obese DIO rats. Taken together with previous studies, these results suggest that obesity may represent a state associated with decreased central sensitivity to neuropeptides such as NMU that increase physical activity and therefore energy expenditure.

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“…OX-A has a high affinity for both receptor subtypes, whereas OX-B shows a 10-fold higher affinity for OX-2R than it does for OX-1R. Immunohistochemical studies have shown that OXimmunoreactive fibers are distributed not only in the hypothalamus but throughout the brain, including the cerebral cortex, thalamus, circumventricular organs, pituitary gland, limbic system and brainstem [15,17,26,64].…”

Section: Newly Identified Gpcr Ligands Involved In Feeding Regulamentioning

confidence: 99%

Distribution and Neuronal Networks of Novel GPCR Ligands in Feeding Regulation

Takenoya

Kageyama

Guan

et al. 2005

Acta Histochem. Cytochem

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Recent studies have shown that a number of novel G-protein coupled receptor (GPCR) ligands localize in brain tissue and perform a range of physiological functions, some of which have been studied and clarified, and others about which less is known. Here, we wish to describe the distribution and localization of GPCR ligands identified thus far and to examine their involvement in neuronal networks, particularly those networks related to feeding regulation. The review analyzes published reports of morphological and physiological data looking mainly at the functional significance of feeding-regulation factors, such as those described by our research group and others, and neuronal interactions among these GPCR ligands in the hypothalamus. Cross-talk among several GPCR ligand-containing neuron types in the hypothalamus plays a role in determining feeding states. We introduce structural and functional characteristics of novel GPCR ligands and summarize the known interactions between several GPCR ligand-containing neuron types and leptin-targeting neurons in the hypothalamus. Finally, we present a new scheme summarizing neuronal networks with regard to feeding regulation in the hypothalamus. Research in this area will play an important role in clarifying neurologically-based causes for appetite dysfunction and establishing therapies for people suffering from such conditions.

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Morphological evidence for neural interactions between leptin and orexin in the hypothalamus

Cited by 55 publications

References 34 publications

Glucokinase Is a Critical Regulator of Ventromedial Hypothalamic Neuronal Glucosensing

Glucokinase Is a Critical Regulator of Ventromedial Hypothalamic Neuronal Glucosensing

Sensitivity of the hypothalamic paraventricular nucleus to the locomotor-activating effects of neuromedin U in obesity

Distribution and Neuronal Networks of Novel GPCR Ligands in Feeding Regulation

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