Tohru Yasuda

Adiponectin protects LPS‐induced liver injury through modulation of TNF‐α in KK‐Ay obese mice

Adiponectin, an adipocytokine, has been identified in adipose tissue, and its receptors are widely distributed in many tissues, including the liver. The present study was performed to clarify the role of adiponectin in lipopolysaccharide (LPS)‐induced liver injury using KK‐Ay obese mice. We analyzed the effects of adiponectin pretreatment on liver injury induced by D‐galactosamine/LPS (GalN/LPS) in KK‐Ay obese mice. GalN/LPS treatment induced significant increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the blood, apoptotic and necrotic changes in hepatocytes, and/or showed a high degree of lethality. The GalN/LPS‐induced liver injury was more pronounced in KK‐Ay obese mice than in lean controls. Pretreatment with adiponectin ameliorated the GalN/LPS‐induced elevation of serum AST and ALT levels and the apoptotic and necrotic changes in hepatocytes, resulting in a reduction in lethality. In addition, pretreatment with adiponectin attenuated the GalN/LPS‐induced increases in serum and hepatic tumor necrosis factor α (TNF‐α) levels and increased peroxisome proliferator‐activated receptor (PPAR) α messenger RNA expression in the liver. Furthermore, abdominal macrophages from KK‐Ay obese mice pretreated with adiponectin in vitro exhibited decreased LPS‐induced TNF‐α production compared with controls. Finally, adiponectin pretreatment also ameliorated TNF‐α‐induced liver injury. In conclusion, these findings suggest that adiponectin prevents LPS‐induced hepatic injury by inhibiting the synthesis and/or release of TNF‐α of KK‐Ay obese mice. (HEPATOLOGY 2004;40:177–184.)

Centrally administered ghrelin suppresses sympathetic nerve activity in brown adipose tissue of rats

To clarify the functional roles of ghrelin in regulating energy balance, we investigated the effects of a central infusion of ghrelin on food intake and the activity of the sympathetic nerve innervating brown adipose tissue (BAT), the site regulating energy expenditure in rodents. A bolus infusion of ghrelin at a dose of 1 nmol/rat into the third cerebral ventricle (i3vt) increased the 4 h cumulative food intake. I3vt infusion of ghrelin (1 nmol/rat) suppressed BAT sympathetic nerve activity, followed by a gradual recovery. In contrast, i3vt infusion of growth hormone (GH) at a dose of 0.5 nmol/rat induced a gradual increase in sympathetic nerve activity. The ghrelin infusion decreased BAT temperature, which recovered gradually, but did not affect rectal temperature. In conclusion, the central administration of ghrelin suppresses energy expenditure and thermogenesis in BAT via its inhibitory effect on BAT sympathetic nerve activity. Simultaneous GH secretion induced by ghrelin treatment may modulate the temporal course of the sympathetic nerve response to ghrelin. The stimulatory and inhibitory effects of ghrelin on energy intake and expenditure, respectively, may induce a positive energy balance, which, in turn, affects adiposity and body weight.

Hypothalamic Melanocortin System Regulates Sympathetic Nerve Activity in Brown Adipose Tissue

To clarify the neuronal mechanism of the hypothalamic melanocortin system in regulating energy metabolism, we investigated the effects of centrally administered α-melanocyte-stimulating hormone (α-MSH) and agouti-related protein (AGRP), an agonist and an antagonist for the melanocortin 4 receptor (MC4-R), respectively, on the activity of sympathetic nerves innervating brown adipose tissue (BAT) and on BAT temperature. A bolus infusion of α-MSH (1 nmol) into the third cerebral ventricle (i3vt) significantly increased sympathetic nerve activity and elevated BAT temperature (P < 0.05). The i3vt infusion of AGRP (1 nmol) gradually suppressed BAT sympathetic nerve activity and was accompanied by a significant reduction in BAT temperature (P < 0.05). In conclusion, the hypothalamic melanocortin system may regulate peripheral energy expenditure, as well as thermogenesis, through its influence on BAT sympathetic nerve activity.

Hypothalamic neuronal histamine regulates sympathetic nerve activity and expression of uncoupling protein 1 mRNA in brown adipose tissue in rats

To clarify how hypothalamic neuronal histamine regulates peripheral energy expenditure, we investigated the effect of infusion of histamine into the third cerebral ventricle or discrete hypothalamic regions on sympathetic nerve activity and expression of uncoupling protein 1 (UCP1) mRNA in brown adipose tissue (BAT). Infusion of histamine (200 nmol) into the third cerebral ventricle of anesthetized rats significantly increased the electrophysiological activity of sympathetic nerves (P<0.01) and UCP1 mRNA expression in the BAT (P<0.05). Microinjection of histamine (10 nmol) into the paraventricular nucleus (PVN) and preoptic area (POA) produced similar significant increases in BAT sympathetic nerve activity (P<0.01 for each). By contrast, injection of histamine into the ventromedial hypothalamic nucleus or lateral hypothalamic area had no effect. We conclude that hypothalamic neuronal histamine may regulate energy expenditure in BAT through the activation of sympathetic nerves. The PVN and/or POA appear to be the principal hypothalamic sites that mediate the stimulatory effect of histamine on this efferent pathway.

Apelin-13 microinjection into the paraventricular nucleus increased sympathetic nerve activity innervating brown adipose tissue in rats

The aim of present study is to clarify the role of apelin in regulating energy homeostasis in brown adipose tissue (BAT). We examined the central effects of apelin-13 on the brain c-fos like immunoreactivity (c-FLI), BAT temperature and the activity of the sympathetic nerve activity innervating BAT in rats. In the hypothalamus, central infusion into the third cerebral ventricle (i3vt) of apelin-13 caused induction of c-FLI in the paraventricular nucleus (PVN) compared with the controls (PBS-treated) group. In addition, microinjection of apelin-13 into the PVN produced significant increases in BAT temperature. Furthermore, microinjection of apelin-13 treatment increased BAT sympathetic nerve activity compared with controls. We conclude that apelin-13 microinjection into PVN increases sympathetic nerve activity innervating BAT.

l-Histidine stimulates sympathetic nerve activity to brown adipose tissue in rats

Hypothalamic neuronal histamine is involved in the central regulation of energy expenditure through the activation of sympathetic nerves innervating brown adipose tissue (BAT). The present study examined the effect of L-histidine, a precursor of neuronal histamine, on BAT sympathetic nerve activity in rats. Infusion of histamine at a dose of 1 nmol/rat into the third cerebroventricle significantly increased BAT sympathetic nerve activity as compared with the effect of phosphate buffered saline (P < 0.05). Intraperitoneal (i.p.) injection of L-histidine (0.3 mmol/rat) also significantly increased BAT sympathetic nerve activity as compared with the effect of PBS (P < 0.05). Pretreatment with an i.p. bolus injection of 224 micromol/kg alpha-fluoromethylhistidine, a suicide inhibitor of the histamine synthesizing enzyme histidine decarboxylase, blocked the stimulatory effect of l-histidine on BAT sympathetic nerve activity. These results indicate that L-histidine regulates BAT sympathetic nerve activity through its conversion into neuronal histamine in the hypothalamus.

Intracerebroventricular administration of urotensin II regulates food intake and sympathetic nerve activity in brown adipose tissue.

To clarify the functional roles of urotensin II in regulating energy balance, we investigated the effects of a central infusion of urotensin II on food intake, uncoupling protein (UCP) 1 mRNA expression, temperature, and sympathetic nervous system activity in brown adipose tissue (BAT), a site that regulates energy expenditure in rodents. A bolus central infusion of urotensin II at a dose of 1 nmol/rat into the third cerebral ventricle decreased food intake (p<0.05). Additionally, urotensin II induced c-Fos-like-immunoreactivity (c-FLI) in the paraventricular nucleus (PVN) as compared with that in the control (phosphate buffered saline [PBS]-treated) group. Furthermore, urotensin II increased BAT UCP 1 mRNA expression (p<0.05). Finally, central infusion of urotensin II significantly increased BAT sympathetic nerve activity, which was accompanied by a significant elevation in BAT temperature (p<0.05) in rats. Taken together, central infusion of urotensin II regulates food intake and BAT sympathetic nerve activity in rats.