Differential control of efferent sympathetic activity revisited.

This article reviews 40 years of research (1970-2010) into the capability of the efferent sympathetic nervous system to display differential responsiveness. Discovered first were antagonistic changes of activity in sympathetic filaments innervating functionally different sections of the cardiovascular system in response to thermal stimulation. During the subsequent four decades of investigation, a multitude of differential sympathetic efferent response patterns were identified, ranging from opposing activity changes at the level of multi-fiber filaments innervating different organs to the level of single fibers controlling functionally different structures in the same organ. Differential sympathetic responsiveness was shown to be displayed in response to exogenous or artificial stimulation of afferent sensory fibers transmitting particular exogenous stimuli, especially those activating peripheral nociceptors. Moreover, sympathetic differentiation was found to be characteristic of autonomic responses to environmental changes by which homeostasis in the broadest sense would be challenged. Heat or cold loads or their experimental equivalents, altered composition of inspired air or changes in blood gas composition, imbalances of body fluid control, and exposure to agents challenging the immune system were shown to elicit differential efferent sympathetic response patterns which often displayed a high degree of specificity. In summary, autonomic adjustments to changes of biometeorological parameters may be considered as representative of the capability of the sympathetic nervous system to exert highly specific efferent control of organ functions by which bodily homeostasis is maintained.

Tympanic temperature is not suited to indicate selective brain cooling in humans: a re-evaluation of the thermophysiological basics.

Selective brain cooling in humans, with venous blood returning from the head surface as the relevant heat sink, was proposed more than two decades ago as a mechanism protecting the brain against damage in hyperthermic conditions. Brain cooling was inferred from decreases of tympanic temperature under the premise that it reflected brain temperature closely, even in conditions of external head cooling. In mammals with a well-developed carotid rete selective brain cooling and its quantitative relevance are experimentally well established by directly monitoring brain temperature. For humans, however, the dispute about the existence and physiological relevance of selective brain cooling has remained unsettled, especially, as far as arguments have been exchanged on the basis of thermophysiological data and model calculations considering brain metabolism, brain hemodynamics and the anatomical preconditions for arterio-venous heat exchange. In this essay two seminal studies in support of the existence of human selective brain cooling in the condition of exercise hyperthermia, with and without dehydration, are re-examined from two points of view: first the stringency of the working hypotheses underlying data evaluation and their subsequent fate. Second the minimum theoretical requirements for data interpretation. The working hypotheses supporting data interpretation in favor of selective brain cooling in humans were heuristic and/or had become questionable at the dates of their application; today, they may be considered as outdated. Data interpretation becomes most conclusive, if tympanic temperature simply is not taken into account.

Heat disorder in Yamanashi Prefecture during the summer from 1995 to 2004.

The incidence of heat disorders in July and August during 10 yr (1995-2004) reported for the population of Yamanashi prefecture was analyzed, with special consideration of an aging society, in relation to levels and patterns of phases with high daily maximal temperatures. There was an increasing tendency for years with hot summers in comparison to preceding decades. Two climatic characteristics associated with increased incidence of heat disorders have become apparent: first, sustained phases of atmospheric temperatures exceeding approximately 32 degrees C, second, rapid onset of phases with high maximal temperature after preceding phases of relatively cool weather. The influence of age expressed itself in a peak of heat disorder incidences among older children and adolescents and in an elevated plateau at ages higher than approximately 60 yr. Up to that age, exertional heat disorders prevailed. At higher ages classical, non-exertional heat disorders constituted an increasing fraction. Lethal outcomes among patients suffering from heat disorder was low. Patients older than 70 yr clearly prevailed among the lethal cases. The frequent occurrence of heat disorders among persons of old age puts emphasis on the importance of maintaining social activity to improve well-being in general and physiological resistance against heat in particular, including adequate fluid supply. Because physiological heat defense is limited in an aging population, adequate air conditioning will gain increasing importance in view of the observed tendency for the increasing occurrence of phases with excessively high atmospheric summer temperatures.

Dose-related steady states of fat loss in long-term leptin-treated ob/ob mice: leptin resistance or desensitization versus counterregulatory signaling.

We tried to unravel why leptin's fat store depleting action levels off in the course of long-term applications. Supplying leptin by minipump infusion for 2 months to ob/ob mice at rates between 115 pmol day(-1) and 460 pmol day(-1) resulted in stable plasma leptin levels between 0.2 ng ml(-1) and 8 ng ml(-1). Initial treatment effects were leptin dose-dependent reductions in food intake and body mass, especially in fat content, followed by re-increases of food intake to levels only 4-18% below pre-treatment levels. Decreased body mass subsequently stabilized dose-dependently with body fat contents between 4% and 33% showing that total fat depletion was not a precondition for the progressive reduction of leptin-induced anorexia. Oxygen consumption measurements excluded contributions of enhanced energy dissipation to fat depletion. Plasma insulin concentrations declined from excessively high pre-treatment levels to steady, leptin dose-dependent levels within the normal range. Temporary anorexia in response to repeated additional 1-day leptin injections (100 pmol g(-1) day(-1)) remained unchanged throughout long-term leptin infusion. Among various alternatives considered to explain the adipostatic equilibrium attained at new, dose-dependent levels under long-term leptin treatment, interaction between the leptin signal and at least one counteracting signal increasing with fat depletion is proposed as the most plausible working hypothesis.

Age-dependent hypothalamic expression of neuropeptides in wild-type and melanocortin-4 receptor-deficient mice.

In young (35- to 56-day-old) and middle-aged (9-mo-old) wild-type (+/+) and melanocortin-4 receptor (MC4R)-deficient (+/-, -/-) mice, expressions of neuropeptide Y (NPY), agouti-related protein (AGRP), pro-opiomelanocortin (POMC), and cocaine-and-amphetamine-regulated transcript (CART) were analyzed in the arcuate nucleus (ARC) and adjacent regions comprising the dorsomedial (DMN) and ventromedial (VMN) nucleus. In the ARC of young mice, NPY and AGRP expression increased and POMC and CART expression decreased with body fat content. Adjusting for the influence of body fat content by ANCOVA showed that the levels of NPY, POMC, and CART were highest and of AGRP lowest in young -/- mice. In the middle-aged mice, feedback from body fat content was weakened. For -/- mice ANCOVA revealed higher NPY and AGRP, lower POMC, and unchanged CART expression levels relative to young -/- mice. In the DMN and VMN, POMC and AGRP signals were absent at each age. CART was expressed in the DMN independent of age, fat content, and genotype. For NPY expression, an age-dependent induction was found in the DMN and VMN; it was absent in the young but present in the middle-aged mice, showing close positive correlations between body fat content and the numbers of NPY-labeled cells which were further enhanced in -/- mice. Thus MC4R deficiency augments age-induced NPY expression in the DMN and VMN with no feedback from body fat content. Negative feedback control by body fat content on ARC neuropeptide expression is present in young animals but vanishes with age and is modulated by MC4R deficiency.

Amylin and glucose co-activate area postrema neurons of the rat.

Glucose is an important metabolic factor controlling feeding behavior. There is evidence that physiologically relevant glucose sensors reside in the caudal hindbrain. The area postrema (AP) in particular, which has been characterized as a receptive site for the anorectic hormone amylin, may monitor blood glucose levels. To determine whether glucose and amylin co-activate the same subset of AP neurons, we performed extracellular single unit recordings from a rat AP slice preparation. In 53% of all AP neurons tested (n=32), the activity was positively correlated to the glucose concentration. Interestingly, there was a coincidental sensitivity (94%) of AP neurons to glucose and amylin, which exerted excitatory effects on these cells. We conclude that the co-sensitivity of AP neurons to glucose and amylin, both increasing in response to food intake, points to the AP as an important hindbrain center for the integration of the metabolic and hormonal control of nutrient intake.

Salmon calcitonin - a potent inhibitor of food intake in states of impaired leptin signalling in laboratory rodents.

To compare the anorectic effectiveness of leptin and the amylin analogue salmon calcitonin (sCT), rodents were treated on 1 day with subcutaneous injections. In chow-fed C57Bl/6J mice, leptin and sCT reduced energy intake and acted additively. After C57Bl/6J mice had become leptin-resistant on being fed chocolate as a palatable high-caloric supplement to chow, their sCT-induced decrease in energy intake was more pronounced than in chow-fed mice with differential changes in the intake of chocolate (strong reduction) and chow (slight increase). Dose-response relationships for sCT-induced reductions in energy intake were analysed in chow-fed C57Bl/6J mice and two obese strains, ob/ob mice and melanocortin-4 receptor knockout (MC4-r-KO) mice, as well as in wild-type and fatty (fa/fa) rats. Compared to C57Bl/6J mice, reduction in food intake induced by sCT was attenuated in MC4-r-KO mice, and nearly absent in ob/ob mice, over the dose range investigated. Compared to C57Bl/6J mice, wild-type rats responded more sensitively to sCT and its efficiency was only slightly reduced in fatty (fa/fa) rats. Thus, while genetically induced failures of leptin signalling reduce the action of sCT, it effectively inhibits the intake of a palatable, high fat-high sugar diet even in states of diet-induced obesity with functional leptin resistance.

Inactivation of the GR in the nervous system affects energy accumulation.

The homeostatic regulation of body weight protects the organism from the negative consequences of starvation and obesity. Glucocorticoids (GCs) modulate this regulation, although the underlying mechanisms remain unclear. To address the role of central GRs in the regulation of energy balance, we studied mice in which GRs have selectively been inactivated in the nervous system. Mutant mice display marked growth retardation. During suckling age this is associated with normal fat deposition causing a 60% temporary increase of percent body fat, compared with control littermates. After weaning, fat and protein depositions are reduced so that adults are both smaller and leaner than their controls. Decreased food intake and, after weaning, reduced metabolic efficiency account for these developmental disturbances. Plasma levels of leptin and insulin, two important energy balance regulators, are elevated in young mutants but normal in adults. Leptin/body fat ratio is higher at all ages, suggesting disturbed control of circulating leptin as a consequence of chronically elevated GC levels in mutant animals. Adult mutants display increased hypothalamic CRH and NPY levels, but peptide levels of melanin concentrating hormone and Orexin A and B are unchanged. The increased levels of plasma GCs and hypothalamic CRH may act as catabolic signals most likely leading to persistently reduced energy accumulation.

Interface Properties of Circumventricular Organs in Salt and Fluid Balance.

The "sensory" circumventricular organs, with their leaky blood-brain barriers, permit contact between brain neurons and blood-borne molecules. Body fluid balance and cardiovascular control involve established interface functions of subfornical organs. Their recently identified target functions for hormones released during digestion suggest that they may coordinate fluid and food intake.