History of hypothalamic research: "The spring of primitive existence".

The central brain region of interest for neuroendocrinology is the hypothalamus, a name coined by Wilhelm His in 1893. Neuroendocrinology is the discipline that studies hormone production by neurons, the sensitivity of neurons for hormones, as well as the dynamic, bidirectional interactions between neurons and endocrine glands. These interactions do not only occur through hormones, but are also partly accomplished by the autonomic nervous system that is regulated by the hypothalamus and that innervates the endocrine glands. A special characteristic of the hypothalamus is that it contains neuroendocrine neurons projecting either to the neurohypophysis or to the portal vessels of the anterior lobe of the pituitary in the median eminence, where they release their neuropeptides or other neuroactive compounds into the bloodstream, which subsequently act as neurohormones. In the 1970s it was found that vasopressin and oxytocin not only are released as hormones in the circulation but that their neurons project to other neurons within and outside the hypothalamus and function as neurotransmitters or neuromodulators that regulate central functions, including the autonomic innervation of all our body organs. Recently magnocellular oxytocin neurons were shown to send not only an axon to the neurohypophysis, but also axon collaterals of the same neuroendocrine neuron to a multitude of brain areas. In this way, the hypothalamus acts as a central integrator for endocrine, autonomic, and higher brain functions. The history of neuroendocrinology is described in this chapter from the descriptions in De humani corporis fabrica by Vesalius (1537) to the present, with a timeline of the scientists and their findings.

Sleep duration associated with mortality in elderly, but not middle-aged, adults in a large US sample.

STUDY OBJECTIVES: To explore age differences in the relationship between sleep duration and mortality by conducting analyses stratified by age. Both short and long sleep durations have been found to be associated with mortality. Short sleep duration is associated with negative health outcomes, but there is little evidence that long sleep duration has adverse health effects. No epidemiologic studies have published multivariate analyses stratified by age, even though life expectancy is 75 years and the majority of deaths occur in the elderly. DESIGN: Multivariate longitudinal analyses of the first National Health and Nutrition Examination Survey using Cox proportional hazards models. SETTING: Probability sample (n = 9789) of the civilian noninstitutionalized population of the United States between 1982 and 1992. PARTICIPANTS: Subjects aged 32 to 86 years. MEASUREMENTS AND RESULTS: In multivariate analyses controlling for many covariates, no relationship was found in middle-aged subjects between short sleep of 5 hours or less and mortality (hazards ratio [HR] = 0.67, 95% confidence interval [CI] 0.43-1.05) or long sleep of 9 hours or more and mortality (HR = 1.04, 95% CI 0.66-1.65). A U-shaped relationship was found only in elderly subjects, with both short sleep duration (HR = 1.27, 95% CI 1.06-1.53) and long sleep duration (HR = 1.36, 95% CI 1.15-1.60) having significantly higher HRs. CONCLUSIONS: The relationship between sleep duration and mortality is largely influenced by deaths in elderly subjects and by the measurement of sleep durations closely before death. Long sleep duration is unlikely to contribute toward mortality but, rather, is a consequence of medical conditions and age-related sleep changes.

Minireview: Circadian control of metabolism by the suprachiasmatic nuclei.

In the present review, first we present the anatomical connections used by the mammalian biological clock to enforce its endogenous rhythmicity on the rest of the body, especially the energy homeostatic systems. Subsequently, we present a number of physiological experiments investigating the functional significance of this neuroanatomical substrate. Together, this overview of experimental data, for a major part derived from our own experiments, reveals a highly specialized organization of connections between the endogenous pacemaker and both the presympathetic and pre-parasympathetic hypothalamic systems, providing the biological clock with a unique opportunity to modulate the balance of sympathetic/parasympathetic inputs to peripheral organs. We hypothesize that a well-balanced autonomic nervous input, differentiated according to the time of day and the body compartment, is an important companion to withstand the progressive burden of the current 24/7 society on our health and well-being.

Selective parasympathetic innervation of subcutaneous and intra-abdominal fat--functional implications.

The wealth of clinical epidemiological data on the association between intra-abdominal fat accumulation and morbidity sharply contrasts with the paucity of knowledge about the determinants of fat distribution, which cannot be explained merely in terms of humoral factors. If it comes to neuronal control, until now, adipose tissue was reported to be innervated by the sympathetic nervous system only, known for its catabolic effect. We hypothesized the presence of a parasympathetic input stimulating anabolic processes in adipose tissue. Intra-abdominal fat pads in rats were first sympathetically denervated and then injected with the retrograde transneuronal tracer pseudorabies virus (PRV). The resulting labeling of PRV in the vagal motor nuclei of the brain stem reveals that adipose tissue receives vagal input. Next, we assessed the physiological impact of these findings by combining a fat pad-specific vagotomy with a hyperinsulinemic euglycemic clamp and RT-PCR analysis. Insulin-mediated glucose and FFA uptake were reduced by 33% and 36%, respectively, whereas the activity of the catabolic enzyme hormone-sensitive lipase increased by 51%. Moreover, expression of resistin and leptin mRNA decreased, whereas adiponectin mRNA did not change. All these data indicate an anabolic role for the vagal input to adipose tissue. Finally, we demonstrate somatotopy within the central part of the autonomic nervous system, as intra-abdominal and subcutaneous fat pads appeared to be innervated by separate sympathetic and parasympathetic motor neurons. In conclusion, parasympathetic input to adipose tissue clearly modulates its insulin sensitivity and glucose and FFA metabolism in an anabolic way. The implications of these findings for the (patho)physiology of fat distribution are discussed.

Sleep duration as a risk factor for diabetes incidence in a large U.S. sample.

STUDY OBJECTIVES: To explore the relationship between sleep duration and diabetes incidence over an 8- to 10-year follow-up period in data from the First National Health and Nutrition Examination Survey (NHANES I). We hypothesized that prolonged short sleep duration is associated with diabetes and that obesity and hypertension act as partial mediators of this relationship. The increased load on the pancreas from insulin resistance induced by chronically short sleep durations can, over time, compromise beta-cell function and lead to type 2 diabetes. No plausible mechanism has been identified by which long sleep duration could lead to diabetes. DESIGN: Multivariate longitudinal analyses of the NHANES I using logistic regression models. SETTING: Probability sample (n=8992) of the noninstitutionalized population of the United States between 1982 and 1992. PARTICIPANTS: Subjects between the ages of 32 and 86 years. MEASUREMENTS AND RESULTS: Between 1982 and 1992, 4.8% of the sample (n=430) were determined by physician diagnosis, hospital record, or cause of death to be incident cases of diabetes. Subjects with sleep durations of 5 or fewer hours (odds ratio = 1.47, 95% confidence interval 1.03-2.09) and subjects with sleep durations of 9 or more hours (odds ratio = 1.52, 95% confidence interval 1.06-2.18) were significantly more likely to have incident diabetes over the follow-up period after controlling for covariates. CONCLUSIONS: Short sleep duration could be a significant risk factor for diabetes. The association between long sleep duration and diabetes incidence is more likely to be due to some unmeasured confounder such as poor sleep quality.

"Diabetes of the elderly" and type 2 diabetes in younger patients: possible role of the biological clock.

The increased prevalence of type 2 diabetes in the aged has been recognized for a long time. Within the last decades, a growing number of younger subjects and even children are prone to develop type 2 diabetes. In both groups, aged and young, the biological clock, located in the suprachiasmatic nucleus of the hypothalamus (SCN) is malfunctioning as evidenced by disturbed sleep cycles and altered circadian rhythms. While elderly patients have an impaired function of the SCN due to the degeneration of neurons, we propose that in younger subjects the clock loses its "feeling" for internal and external rhythms caused by the modern lifestyle. Sleeping late and less coupled with constant metabolic excess alter both internal and external environmental stimuli to the brain. In response to these alterations, the rhythm of the biological clock is disrupted which may lead to the metabolic syndrome and type 2 diabetes.

Tracing from fat tissue, liver, and pancreas: a neuroanatomical framework for the role of the brain in type 2 diabetes.

The hypothalamus uses hormones and the autonomic nervous system to balance energy fluxes in the body. Here we show that the autonomic nervous system has a distinct organization in different body compartments. The same neurons control intraabdominal organs (intraabdominal fat, liver, and pancreas), whereas sc adipose tissue located outside the abdominal compartment receives input from another set of autonomic neurons. This differentiation persists up to preautonomic neurons in the hypothalamus, including the biological clock, that have a distinct organization depending on the body compartment they command. Moreover, we demonstrate a neuronal feedback from adipose tissue that reaches the brainstem. We propose that this compartment-specific organization offers a neuroanatomical perspective for the regional malfunction of organs in type 2 diabetes, where increased insulin secretion by the pancreas and disturbed glucose metabolism in the liver coincide with an augmented metabolic activity of visceral compared with sc adipose tissue.

Organization of circadian functions: interaction with the body.

The hypothalamus integrates information from the brain and the body; this activity is essential for survival of the individual (adaptation to the environment) and the species (reproduction). As a result, countless functions are regulated by neuroendocrine and autonomic hypothalamic processes in concert with the appropriate behaviour that is mediated by neuronal influences on other brain areas. In the current chapter attention will be focussed on fundamental hypothalamic systems that control metabolism, circulation and the immune system. Herein a system is defined as a physiological and anatomical functional unit, responsible for the organisation of one of these functions. Interestingly probably because these systems are essential for survival, their function is highly dependent on each other's performance and often shares same hypothalamic structures. The functioning of these systems is strongly influenced by (environmental) factors such as the time of the day, stress and sensory autonomic feedback and by circulating hormones. In order to get insight in the mechanisms of hypothalamic integration we have focussed on the influence of the biological clock; the suprachiasmatic nucleus (SCN) on processes that are organized by and in the hypothalamus. The SCN imposes its rhythm onto the body via three different routes of communication: 1.Via the secretion of hormones; 2. via the parasympathetic and 3.via the sympathetic autonomous nervous system. The SCN uses separate connections via either the sympathetic or via the parasympathetic system not only to prepare the body for the coming change in activity cycle but also to prepare the body and its organs for the hormones that are associated with such change. Up till now relatively little attention has been given to the question how peripheral information might be transmitted back to the SCN. Apart from light and melatonin little is known about other systems from the periphery that may provide information to the SCN. In this chapter attention will be paid to e.g. the role of the circumventricular organs in passing info to the SCN. Herein especially the role of the arcuate nucleus (ARC) will be highlighted. The ARC is crucial in the maintenance of energy homeostasis as an integrator of long- and short-term hunger and satiety signals. Receptors for metabolic hormones like insulin, leptin and ghrelin allow the ARC to sense information from the periphery and signal it to the central nervous system. Neuroanatomical tracing studies using injections of a retrograde and anterograde tracer into the ARC and SCN showed a reciprocal connection between the ARC and the SCN which is used to transmit feeding related signals to the SCN. The implications of multiple inputs and outputs of the SCN to the body will be discussed in relation with metabolic functions.

The metabolic syndrome: a brain disease?

The incidence of obesity with, as consequence, a rise in associated diseases such as diabetes, hypertension and dyslipidemia--the metabolic syndrome--is reaching epidemic proportions in industrialized countries. Here, we provide a hypothesis that the biological clock which normally prepares us each morning for the coming activity period is altered due to a modern life style of low activity during the day and late-night food intake. Furthermore, we review the anatomical evidence supporting the proposal that an unbalanced autonomic nervous system output may lead to the simultaneous occurrence of diabetes type 2, dyslipidemia, hypertension and visceral obesity.

Central nervous determination of food storage--a daily switch from conservation to expenditure: implications for the metabolic syndrome.

Here, we present a neuroendocrine concept to review the circularly interacting energy homeostasis system between brain and body. Body-brain interaction is circular because the brain immediately integrates an input to an output, and because part of this response may be that the brain modulates the sensitivity of this perception. First, we describe how the brain senses the body through neurons and blood-borne factors. Direct neuronal connections report the state of various organs. In addition, humoral factors are perceived by the blood-brain barrier and circumventricular organs. We describe how circulating energy carriers are sensed and what signals reach the brain during food intake, exercise and an immune response. We describe that the brain regulates the homeostatic process at two fundamentally different levels during the active and inactive states. The unbalanced output of the brain in the metabolic syndrome is discussed in relation with such circadian rhythms and with regional activity of the autonomic nervous system. In line with the above, we suggest a new approach for the diagnosis and therapy of the metabolic syndrome.

An individual, community-based treatment for obese children and their families: the solution-focused approach.

BACKGROUND: This study evaluates an individual, community-based treatment for obese children and their families. In this program, a treatment team applied solution-focused techniques to develop a custom-made treatment plan in collaboration with the participants. The treatment plan consisted of community-based lifestyle activities. METHODS: 559 obese children with an average BMI z-score of 2.76 ± 0.54 took part in the 12-month study, and 372 children with an average BMI z-score of 2.75 ± 0.52 took part in the 24-month study. At the start of the study, ethnicity and special school needs were recorded. Before, after 12 months, and after 24 months of the treatment, body weight and height were measured. The effect of the treatment on body weight was evaluated using BMI z-scores. RESULTS: 291 children (52%) completed 12 months of treatment, whereas 22 children (4%) were dismissed earlier due to a good response. After 12 months, the children showed a significant decrease in BMI z-score by 0.16 (95% confidence interval (CI) 0.11-0.20; p < 0.005). After 24 months, 103 children (28%) were participating in the program, with a significant decrease in BMI z-score of 0.15 (95% CI 0.07-0.22; p < 0.005). 50 children (13%) were dismissed before the end of the second year due to significant weight loss (standard deviation z-score reduction -0.38; 95% CI 0.30-0.46; p < 0.005; with an average treatment duration of 12.9 ± 6.4 months). There was a negative correlation of age and reduction in BMI z-score: children younger than 6 years showed a decrease in BMI z-score of 0.45 (95% CI 0.26-0.65) and 0.31 (95% CI 0.11-0.53) after 12 and after 24 months, respectively. CONCLUSIONS: Children showed a significant decrease in BMI z-score after the treatment. We found a negative correlation of age and weight loss. Special attention to patients with a high risk of drop-out might further improve these results. We advise a referral to obesity treatment as early as possible since a 'wait and see' policy might have adverse results in obese children.

Circadian rhythms in white adipose tissue.

Adipose tissue is an important endocrine organ. It is involved in the regulation of energy metabolism by secreting factors (adipokines) that regulate appetite, food intake, glucose disposal, and energy expenditure. Many of these adipokines display profound day/night rhythms, and accumulating evidence links disruption of these rhythms to metabolic diseases such as obesity and type 2 diabetes. Here, we briefly present the circadian system, describe the development of white adipose tissue (WAT) and its depot-specific characteristics and innervation, we discuss energy storage in WAT and, lastly, review recent findings that link circadian rhythmicity to adipose tissue biology and obesity.

To be, or not to be obese - that's the challenge: a hypothesis on the cortical inhibition of the hypothalamus and its therapeutical consequences.

Today, obesity is the most urgent unsolved medical problem, with the threat of a decreased life expectancy rate for the first time in medical history. Many obese subjects try to lose weight by dieting and exercising, without success on a long term basis. The only therapy with some effect is bariatric surgery with the impact of sustainable adverse effects only suitable in morbid obesity. Why are the therapies to treat obesity not working? Within the last years, we have become more aware of the role of the brain in energy homeostasis. The three main players within the brain controlling our weight are the cortex for cognition, hypothalamus for vital body functions and limbic-reward system for emotions. One hypothesizes that the failure of the cortex to inhibit the hypothalamus is the main cause of obesity. The evolutionary old hypothalamus constantly seeks for a positive energy balance, always in endeavor to avoid any energy shortage in the future. The hypothalamus is executing its tasks in a parallel mode. It can coordinate a set of vital routines independently, yet simultaneously. For e.g., energy balance, salt balance, body temperature and sleep are executed even in a coma. The hypothalamus is primitive but stable. The cortex in humans is, compared to rodents, much bigger and more complex, while the hypothalamus bears more similarities between these two species. The cortex in humans is evolutionary younger and represents higher cognition, an unique human feature. In contrast to the hypothalamus, the cortex focuses on one problem at a time, thus functioning on an attention-based manner. Due to this serial mode, the cortex uses a large part of its capacity for one problem at a time. Therefore, it can solve more complex calculations than the hypothalamus by thinking about one problem after another. It is even strong enough to veto the hypothalamus, if necessary. If the concentration on weight loss is distorted, the hypothalamus is free of inhibition by the cortex, and the subject will gain weight again. It is suggested that this is why diets do not work in the long term. In anorexic patients, the cortex is fully occupied to control the hypothalamus resulting in extreme weight loss. In obese subjects, the cortex is less disciplined and the hypothalamus will take control again to stimulate positive energy balance. From this viewpoint, the limbic-reward system interacts both with the hypothalamus and the cortex to achieve demands by emotional motivation. The last part of this paper describes a therapeutic strategy based on this hypothesis. We propose a dual approach to fight obesity. First, interventions should be implemented that remind the cortex to control the hypothalamus and second, to stimulate physiological feedback to the hypothalamus.