Manipulating central nervous mechanisms of food intake and body weight regulation by intranasal administration of neuropeptides in man
Introduction
Body adiposity is individually regulated within narrow margins, resulting in a remarkably constant set-point to which body weight after fat loss or gain will in most cases eventually return [1]. In recent years, research on the balancing of food intake and energy expenditure by the central nervous system (CNS) has made considerable progress. The role of circulating insulin and leptin as endocrine messengers which report the level of energy stored as body fat to the brain has been well established, and the complex hypothalamic networks processing these signals and ultimately leading to reduced or increased caloric intake has been elucidated [2], [3], [4]. At the same time, intranasal administration has made it possible to deliver some of these neuropeptidergic messengers directly to the brain without substantial absorption into the blood stream [5], [6] and, thus, the manipulation of CNS body weight regulation in humans has become feasible.
Insulin as well as leptin fulfill the criteria identifying a compound as ‘adiposity signal’ [4]: Their peripheral levels are proportional to body adiposity and decrease during fasting [7], [8]. High densities of insulin and leptin receptors are found in brain regions important to food intake regulation, suggesting that, after crossing the blood–brain barrier (BBB), they play an essential role in modulating caloric intake [9], [10]. Furthermore, meals increase the concentration of insulin in the cerebrospinal fluid (CSF) and hypothalamus [11]. The administration of both leptin, which is primarily produced by white adipose tissue, and insulin, which is released by pancreatic beta-cells, reduces food intake and body adiposity [12], [13].
In the arcuate nucleus of the hypothalamus, a highly integrated neuropeptidergic network constitutes the downstream signaling system for insulin and leptin, resulting in a balanced regulation of anabolic and catabolic pathways [3], [4], [9]. Anabolic pathways trigger food intake (i.e., they are orexigenic) and decrease energy expenditure—leading to weight gain—while catabolic signal transduction increases caloric intake (i.e., has anorexigenic properties), which, in combination with increased energy expenditure, leads to weight loss (Fig. 1). Neurons synthesizing alpha-melanocyte-stimulating hormone (alpha-MSH), a melanocortin derived from pre-proopiomelanocortin (POMC), are essential for catabolic signal transduction [14], [15]. Leptin and insulin increase POMC gene expression in the arcuate nucleus [16], [17], and prolonged systemic administration of melanocortin-related peptides by intraperitoneal injections in POMC-deficient obese mice has been consistently found to reduce body weight [18]. It is assumed that the ability of leptin and insulin to reduce food intake when administered to the CNS essentially relies on the stimulation of arcuate POMC neurons, resulting in the release of alpha-MSH, the natural ligand of the melanocortin receptor 4 (MC4-R) [19], [20]. Among the five subtypes of the melanocortin receptors (MC1-R to MC5-R), the MC4-R appears to be most closely linked to the regulation of body weight [21], [22]. Thus, genetic deficiency of the MC4-R in mice is accompanied by hyperphagia, hyperinsulinemia, hyperglycemia and obesity [21].
Among the anabolic structures, the neuropeptide Y (NPY) and agouti-related protein (AgRP) systems are of major importance. AgRP, which is released in arcuate neurons that coexpress NPY [23], exerts at least some of its anabolic effects through a competitive antagonism of the natural ligand alpha-MSH at the melanocortin receptor (MC-R) [24]. AgRP and NPY neurons are inhibited by leptin [23], [25]. A lack of insulin presumably activates the AgRP/NPY system [26], [27]. NPY, assumed to be the most potent orexigenic signal [28], which accounts especially for meal size [29], exerts its anabolic effects predominantly via the NPY Y1/Y5 receptors that are found in high concentrations in the paraventricular nucleus, a site which is essential for the regulation of energy homeostasis [28], [30]. Discussing the pathways between hypothalamic nuclei and the caudal brainstem, where neural, endocrine and duodenal nutrient signals converge to terminate single meals, is beyond the scope of this article. A number of excellent reviews provide an in-depth account of this topic [3], [8], [31].
The model of hypothalamic weight regulation described above essentially relies on data gathered in animal experiments. The increasing prevalence of obesity underlines the urge to broaden our understanding of how body weight is regulated in the CNS in humans and to develop effective therapeutic means to induce weight loss [32]. Experimental and therapeutic use of neuropeptides involved in the central nervous control of body weight in humans has been greatly hindered, because following systemic administration these compounds do not readily pass the BBB, and in circulating blood may evoke potent hormone-like side effects [33], [34]. Our group has shown in humans that the intranasal administration of peptides, like insulin and melanocortin4–10 (MSH/ACTH4–10), an MC4-R agonist, allows direct access to the CSF compartment within 30 min, bypassing uptake into the bloodstream [5] (Fig. 2). Using the intranasal route of peptide administration, in a series of studies, we scrutinized the effects of the adiposity signal insulin and of NPY and MSH/ACTH4–10, with the latter two representing prominent orexigenic and anorexigenic hypothalamic downstream messengers. In the first study, NPY was shown to acutely attenuate electrocortical signs of meal-related satiety. Studies 2 and 3 proved the ability of prolonged administration of insulin and MSH to induce weight loss in healthy humans. On the contrary, overweight subjects do not lose body fat after MSH administration, as was shown in Study 4. In the following review, these studies, which have been or will be published elsewhere, are presented in somewhat greater detail.
Section snippets
Study 1: NPY and cortical direct current potential correlates of satiety
Control of eating behavior relies not only on hypothalamic, but also on limbic and neocortical structures. In the orbitofrontal cortex of monkeys, taste-sensitive neurons have been found that decrease their activity during satiety [35]. Human studies on regional cerebral blood flow (rCBF) in hungry subjects yielded increased activity in structures such as the insular and orbitofrontal cortex upon taste receptor stimulation [36], while satiation corresponded with activation of the ventromedial
Study 2: insulin and body weight regulation in normal-weight men
In animals, administration of insulin to the CNS reduces food intake and body weight [13] while its antagonization has reversed effects [50]. Accordingly, switching off neuronal insulin receptors increases body weight and susceptibility to diet-induced obesity [51]. In animals, the catabolic effects of insulin are well documented [3], and there are some reports on the disproportional relationship between insulin secretion and weight gain in humans[52], [53], but to our knowledge, there is no
Study 3: MSH/ACTH4–10 and body weight regulation in normal-weight humans
Among the neurotransmitter systems that stimulate catabolic effects, the melanocortin system of the arcuate nucleus of the hypothalamus is of major importance. In humans, various MC4-R mutations have been identified mostly in extremely obese individuals with BMIs above the 99th percentile [60], [61]. Obesity is also a key symptom of human patients and mutant mice with deficient synthesis of melanocortins [18], [62]. Moreover, in the latter animal model, daily treatment with an MSH/ACTH agonist
Study 4: MSH/ACTH4–10 and body weight regulation in overweight humans
As seen in the foregoing study, the intranasal administration of the melanocortin core fragment MSH/ACTH4–10 in normal-weight adults over a period of 6 weeks resulted in a significant reduction of body weight and body fat. This fourth study was performed to examine this effect in overweight humans, targeting at an evaluation of a possible therapeutic use of the compound (Smolnik et al., submitted for publication).
Twenty-six overweight men (BMI: 29.72±0.43 kg/m2), who were otherwise healthy,
Conclusions
The results briefly described here demonstrate that central nervous regulation of body weight and of satiety and food intake may be modulated by intranasal administration of neuropeptides. A distinct attenuation of DC-potential changes assumed to reflect satiety upon NPY administration points to the potential ability of this anabolic messenger to increase food intake. Long-term intranasal administration of insulin exerts a catabolic impact on body weight and body fat stores. Decreased
Acknowledgments
We are grateful to A. Hatke, V. Merl, R. Smolnik, I. v. Lützau, A. Otterbein, H. Ruf and C. Otten for their skilled technical assistance. Aero Pump, Hochheim, Germany, generously provided us with precision nasal air pumps. Supported by the Deutsche Forschungsgemeinschaft.
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