Since the observation by Claude Bernard in the 1850 s that puncture of the floor of the fourth ventricle in dogs results in the appearance of transient glucosuria, the central nervous system (CNS) has been implicated in the control of certain metabolic processes of energy homeostasis mainly through neuroendocrine systems. After its recent discovery, leptin, an adipocyte hormone, has been proposed to signal the CNS to modulate autonomic outflow and food intake, leading to alterations of energy metabolism [1,2]. Leptin has been suggested to increase sympathetic outflow and disturbances of leptin signalling lead to Diabetologia (2000) 43: 533±549 ReviewsNew insights into sympathetic regulation of glucose and fat metabolism AbstractThe autonomic nervous system modulates glucose and fat metabolism through both direct neural effects and hormonal effects. This review presents recent concepts on the sympathetic regulation of glucose and fat metabolism. Focally released norepinephrine from sympathetic nerves is likely to increase glucose uptake in skeletal muscle and adipose tissues independent of insulin but norepinephrine does not contribute so much as epinephrine to hepatic glucose production. Epinephrine increases hepatic glucose production and inhibits insulin secretion and the glucose uptake by tissues that is induced by insulin. Additionally, catecholamines can increase thermogenesis and lipolysis, leading to increased energy expenditure and decreased fat stores. It is likely that b-(b3)-adrenergic receptors mediate these responses. Alterations of central neurotransmission and environmental factors can change the relative contribution of sympathetic outflow to the pancreas, liver, adrenal medulla and adipose tissues, leading to the modulation of glucose and fat metabolism. Recent studies have proposed that leptin, an adipocyte hormone, affects the central nervous system to increase sympathetic outflow independent of feeding. The effects of leptin on glucose and fat metabolism could be in part mediated by the sympathetic nervous system. Studies using mice with a genetic disruption of serotonin 5-HT2 c receptor indicate that central neural mechanisms in the regulation of sympathetic outflow and satiety could be dissociated. Abnormalities of sympathetic effects, including disturbances of leptin and b3-adrenergic receptor signalling, are likely to cause obesity and impaired glucose tolerance in rodents and humans. These findings indicate that dysfunction of the sympathetic nervous system could predispose to obesity and Type II (non-insulin-dependent) diabetes mellitus. [Diabetologia (2000) 43: 533±549]

Brain serotonin and leptin signaling contribute substantially to the regulation of feeding and energy expenditure. Here we show that young adult mice with a targeted mutation of the serotonin 5-HT2C receptor gene consume more food despite normal responses to exogenous leptin administration. Chronic hyperphagia leads to a 'middle-aged'-onset obesity associated with a partial leptin resistance of late onset. In addition, older mice develop insulin resistance and impaired glucose tolerance. Mutant mice also responded more to high-fat feeding, leading to hyperglycemia without hyperlipidemia. These findings demonstrate a dissociation of serotonin and leptin signaling in the regulation of feeding and indicate that a perturbation of brain serotonin systems can predispose to type 2 diabetes.

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Interleukin-6 (IL-6) not only regulates a variety of immune functions, but also is the most potent cytokine in inducing the hepatic acute phase proteins. We determined the effect of IL-6 on serum lipid levels and the mechanism of IL-6-induced hypertriglyceridemia in rats. Intravenous administration of IL-6 (0.1-10 micrograms/200 g BW) increased serum triglyceride levels in a dose-dependent manner. One hour after IL-6 administration, serum triglyceride levels were increased, with peak values at 2 h (2.2-fold increase). Serum cholesterol levels also increased, but the effect was delayed, first occurring at 4 h and peaking at 8 h (1.24-fold increase). IL-6 treatment increased hepatic triglyceride secretion without decreasing the clearance of triglyceride-rich lipoproteins, indicating that the hypertriglyceridemia was due to increased secretion by the liver. Furthermore, IL-6 stimulates lipolysis, and the increased delivery of FFA to the liver significantly contributed to the IL-6-induced hypertriglyceridemia. Neither alpha 1- nor beta-adrenergic receptor antagonists affected the hypertriglyceridemia induced by IL-6, whereas previous studies have shown that endotoxin-induced hypertriglyceridemia was blocked by alpha-adrenergic receptor antagonists. These results demonstrate that IL-6 induces hypertriglyceridemia by stimulating hepatic triglyceride secretion independent of endogenous catecholamines. Thus, changes in hepatic triglyceride metabolism are another acute phase response that can be induced by IL-6.

Social isolation is associated with increased risks of mortality and morbidity. In this study, we show that chronic individual housing accelerated body weight gain and adiposity in KK mice but not C57BL6J mice, and fully developed diabetes in KKA(y) mice. Individually housed KK and KKA(y) mice increased body weight gain over the initial 2 wk without increased daily average food consumption compared with group-housed animals. The individually housed KK and KKA(y) mice then gradually increased food consumption for the next 1 wk. The chronic social isolation-induced obesity (SIO) was associated with hyperleptinemia and lower plasma corticosterone and active ghrelin levels but not hyperinsulinemia. Elevated plasma leptin in the SIO suppressed expression of 5-HT2C receptor in white adipose tissue. The SIO was also associated with decreased expression of beta3-adrenergic receptors in white adipose tissue and hypothalamic leptin receptor, which might be secondary to the enhanced adiposity. Interestingly, social isolation acutely reduced food consumption and body weight gain compared with group-housed obese db/db mice with leptin receptor deficiency. Social isolation-induced hyperglycemia in KKA(y) mice was associated with increased expression of hepatic gluconeogenetic genes independent of insulin. These findings suggest that social isolation promotes obesity due to primary decreased energy expenditure and secondary increased food consumption, which are independent of the disturbed leptin signaling, in KK mice, and develops into insulin-independent diabetes associated with increased expression of hepatic gluconeogenetic genes in KKA(y) mice. Thus, social isolation can be included in the environmental factors that contribute to the development of obesity and type 2 diabetes.

1 The present study was undertaken to elucidate the mechanism(s) of hypoglycaemia caused by quinolone antibiotics. We investigated the effects of various quinolone antibiotics on insulin release in rat pancreatic islets. 2 At a non-stimulatory concentration of 3 mM glucose, lomefloxacin (LFLX) or sparfloxacin at 1 mM and pipemidic acid (0.1-1 mM) induced slight insulin release but tosufloxacin or enoxacin up to 100 gtM did not. 3 At the stimulatory concentration of 10 mm glucose, all quinolones augmented insulin release in a dose-dependent manner. LFLX (100 gM) shifted the dose-response curve of glucose-induced insulin release to the left without altering the maximal response.4 At 10 mM glucose, LFLX (100 gM) increased insulin release augmented by forskolin (5 ,M) or 12-0-tetradecanoyl phorbol-13-acetate (100 nM) but not by raising the K' concentration from 6 to 25 mM.5 Verapamil (50 gM) or diazoxide (50-400 gM) antagonized the insulinotropic effect of LFLX. 6 These data suggest that quinolone antibiotics may cause hypoglycaemia by increasing insulin release via blockade of ATP-sensitive K' channels.

We have observed late-onset obesity in mutant mice lacking the serotonin 5-HT 2C receptor. Despite chronically elevated food intake, young adult mutants exhibit neither elevated adiposity nor altered glucose or fat homeostasis. However, obesity subsequently develops after 6 months of age without increases in their level of hyperphagia. In this study, we investigated determinants of energy expenditure in 5-HT 2C receptor mutant mice. Young adult mutants displayed patterns of elevated activity levels that were enhanced by fasting and tightly associated with repeated visits to a food source. Surprisingly, subsequent obesity development occurred despite persisting locomotor hyperactivity and without age-related declines in resting metabolic rate. Rather, substantial reductions in the energy cost of locomotor activity (LA) were observed in 5-HT 2C receptor mutant mice. Moreover, both mutant and wild-type mice displayed age-related declines in the energy cost of LA, indicating that this process may be regulated by both aging and serotonergic signaling. These results indicate that a mutation of the 5-HT 2C receptor gene (htr2c) increases LA, which contributes to the maintenance of normal body composition in young adult mutants despite their hyperphagia. Moreover, age-dependent reductions in the energy cost of physical activity could contribute to the subsequent development of late-onset obesity in 5-HT 2C receptor mutant mice. Diabetes 52: 315-320, 2003 M ultiple lines of evidence indicate that the monoamine serotonin (5-hydroxytryptamine [5-HT]) exerts powerful influences on feeding behavior (1,2). Treatments that enhance brain serotonergic transmission, such as the prototypical appetite suppressant fenfluramine, serotonin reuptake blockers, the serotonin precursor L-tryptophan, and nonspecific 5-HT receptor agonists, suppress food intake. Conversely, treatments that reduce serotonergic neural activity, such as intraventricular injections of the serotonergic neurotoxin 5,7-dihydroxytryptamine and lesions of the serotonergic raphe B8 cell group, produce chronic hyperphagia and weight gain. Several lines of evidence implicate the 5-HT 2C receptor in the anorectic effects of brain serotonergic systems (1-4). For example, the nonselective 5-HT receptor agonist m-chlorophenylpiperazine and the fenfluramine metabolite norfenfluramine have appetite suppressant actions that are blocked by 5-HT 2C receptor antagonist compounds.The 5-HT 2C receptor is expressed in many brain regions, and its expression is restricted to the central nervous system (5,6). To investigate the functional roles of this receptor subtype, we have generated a line of mice bearing a mutation of the htr2c gene. These animals display hyperphagia, reduced sensitivity to the anorectic effects of m-chlorophenylpiperazine and dexfenfluramine, enhanced susceptibility to type 2 diabetes, and a late-onset obesity syndrome (2,7,8). Despite their chronically elevated food intake, young adult mutants exhibit neither elevated adiposity nor alterations in plasma levels...

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