In mammals, circadian oscillators exist not only in the suprachiasmatic nucleus, which harbors the central pacemaker, but also in most peripheral tissues. It is believed that the SCN clock entrains the phase of peripheral clocks via chemical cues, such as rhythmically secreted hormones. Here we show that temporal feeding restriction under light–dark or dark–dark conditions can change the phase of circadian gene expression in peripheral cell types by up to 12 h while leaving the phase of cyclic gene expression in the SCN unaffected. Hence, changes in metabolism can lead to an uncoupling of peripheral oscillators from the central pacemaker. Sudden large changes in feeding time, similar to abrupt changes in the photoperiod, reset the phase of rhythmic gene expression gradually and are thus likely to act through a clock-dependent mechanism. Food-induced phase resetting proceeds faster in liver than in kidney, heart, or pancreas, but after 1 wk of daytime feeding, the phases of circadian gene expression are similar in all examined peripheral tissues.

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Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus

Cytokine production by the immune system contributes importantly to both health and disease. The nervous system, via an inflammatory reflex of the vagus nerve, can inhibit cytokine release and thereby prevent tissue injury and death. The efferent neural signaling pathway is termed the cholinergic antiinflammatory pathway. Cholinergic agonists inhibit cytokine synthesis and protect against cytokine-mediated diseases. Stimulation of the vagus nerve prevents the damaging effects of cytokine release in experimental sepsis, endotoxemia, ischemia/reperfusion injury, hemorrhagic shock, arthritis, and other inflammatory syndromes. Herein is a review of this physiological, functional anatomical mechanism for neurological regulation of cytokine-dependent disease that begins to define an immunological homunculus.

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Physiology and immunology of the cholinergic antiinflammatory pathway

The occurrence of sulfonamide and macrolide antimicrobials, as well as trimethoprim, was investigated in conventional activated sludge treatment. Average daily loads in untreated wastewater correlated well with those estimated from annual consumption data and pharmacokinetic behavior. Considerable variations were found during a day, and seasonal differences seem to occur for the macrolides, probably caused by a higher consumption of these substances in winter. The most predominant macrolide and sulfonamide antimicrobials were clarithromycin and sulfamethoxazole, respectively. In the case of sulfamethoxazole, the main human metabolite, N4-acetylsulfamethoxazole, was included as an analyte, accounting for up to 86% of the total load in untreated wastewater. The results obtained illustrate the importance of considering retransformable substances, for example human metabolites, when investigating the behavior and fate of pharmaceuticals. Average concentrations of sulfapyridine, sulfamethoxazole, trimethoprim, azithromycin, and clarithromycin in activated sludge ranged between 28 and 68 microg/kg of dry weight. Overall the sorption to activated sludge was shown to be low for the investigated antimicrobials, with estimated sorption constants for activated sludge below 500 L/kg. Elimination in activated sludge treatment was found to be incomplete for all investigated compounds. In final effluents, the median concentrations for sulfamethoxazole and clarithromycin were 290 and 240 ng/L, respectively.

Occurrence and sorption behavior of sulfonamides, macrolides, and trimethoprim in activated sludge treatment.

The vagus nerve has an important role in regulation of metabolic homeostasis, and efferent vagus nerve-mediated cholinergic signalling controls immune function and proinflammatory responses via the inflammatory reflex. Dysregulation of metabolism and immune function in obesity are associated with chronic inflammation, a critical step in the pathogenesis of insulin resistance and type 2 diabetes mellitus. Cholinergic mechanisms within the inflammatory reflex have, in the past 2 years, been implicated in attenuating obesity-related inflammation and metabolic complications. This knowledge has led to the exploration of novel therapeutic approaches in the treatment of obesity-related disorders.

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The vagus nerve and the inflammatory reflex—linking immunity and metabolism

https://pure.rug.nl/ws/files/3391893/1987ProgrNeurobiolLuiten.pdf

The hypothalamus, intrinsic connections and outflow pathways to the endocrine system in relation to the control of feeding and metabolism.

Cholinergic stimulation of the lateral hypothalamic neurons with intrahypothalamic microinjections of acetylcholine or carbachol caused a marked increase in the content of the active form of glycogen (starch) synthase in the liver. Total activity of the enzyme (active plus inactive forms) was not increased significantly. The lowest effective dose of acetylcholine was 5 X 10(-10) mole, and the optimum dose was 5 X 10(-9) mole. Similar applications of other neurotransmitters, such as norepinephrine, dopamine, serotonin, and gamma-aminobutyric acid, did not affect the enzyme's activity.

Cholinergic stimulation of the rat hypothalamus: effects of liver glycogen synthesis

The effects of electrical and chemical stimulations of the hypothalamus on the plasma levels of glucagon, insulin, and glucose were studied in undisturbed and free-moving rabbits. Electrical stimulation of the ventromedial hypothalamic nucleus (VMH) caused a marked increase in the circulating level of glucagon coincident with a rapid rise in the glucose level. The level of insulin did not increase during VMH stimulation, but increased after cessation of stimulation. Electrical stimulation of the lateral hypothalamic nucleus (LHN), on the other hand, did not alter the plasma level of either hormone. Microinjection of a minute amount of acetylcholine into the VMH led to a rapid increase in plasma glucagon, with a gradual rise in plasma glucose, but no significant change in the insulin level. The responses of glucagon and glucose to acetylcholine were almost completely blocked by previous treatment of the VMH with hexamethonium, but not with atropine. Microinjections of epinephrine and norepinephrine into th...

Koichi Ishikawa

Papers

Cholinergic stimulation of the rat hypothalamus: effects of liver glycogen synthesis

Modulation by the hypothalamus of glucagon and insulin secretion in rabbits: studies with electrical and chemical stimulations.

Daily rhythms of glycogen synthetase and phosphorylase activities in rat liver: Influences of food and light

Hypothalamic control of liver glycogen metabolism in adult and aged rats.

Chemical coding of the hypothalamic neurones in metabolic control. I. Acetylcholine-sensitive neurones and glycogen synthesis in liver