Outcome in anorexia nervosa remains poor and a new way of looking at this condition is therefore needed. To this aim, we review the effects of food restriction and starvation in humans. It is suggested that body weight remains stable and relatively low when the access to food requires a considerable amount of physical activity. In this condition, the human homeostatic phenotype, body fat content is also low and as a consequence, the synthesis and release of brain neurotransmitters are modified. As an example, the role of neuropeptide Y is analyzed in rat models of this state. It is suggested that the normal behavioral role of neuropeptide Y is to facilitate the search for food and switch attention from sexual stimuli to food. Descriptive neuroendocrine studies on patients with anorexia nervosa have not contributed to the management of the patients and the few studies in which hormones have been administered have, at best, reversed an endocrine consequence secondary to starvation. In a modified framework for understanding the etiology and treatment of anorexia nervosa it is suggested that the condition emerges because neural mechanisms of reward and attention are engaged. The neural neuropeptide Y receptor system may be involved in the maintenance of the behavior of eating disorder patients because the localization of these receptors overlaps with the neural systems engaged in cue-conditioned eating in limbic and cortical areas. The eating behavior of patients with anorexia nervosa, and other eating disorders as well, is viewed as a cause of the psychological changes of the patients. Patients are trained to re-learn normal eating habits using external support and as they do, their symptoms, including the psychological symptoms, dissolve. (C) 2008 Elsevier Inc. All rights reserved.

The hypothesis that treatment with neuropeptide Y (NPY) can increase running activity and decrease food intake and body weight was tested. Female rats with a running wheel lost more weight than sedentary rats and ran progressively more as the availability of food was gradually reduced. When food was available for only 1h/day, the rats lost control over body weight. Correlatively, the level of NPY mRNA was increased in the hypothalamic arcuate nucleus. This phenomenon, activity-based-anorexia, was enhanced by intracerebroventricular infusion of NPY in rats which had food available during 2h/day. By contrast, NPY stimulated food intake but not wheel running in rats which had food available continuously. These findings are inconsistent with the prevailing theory of the role of the hypothalamus in the regulation of body weight according to which food intake is a homeostatic process controlled by "orexigenic" and "anorexigenic" neural networks. However, the finding that treatment with NPY, generally considered an "orexigen", can increase physical activity and decrease food intake and cause a loss of body weight is in line with the clinical observation that patients with anorexia nervosa are physically hyperactive and eat only little food despite having depleted body fat and up-regulated hypothalamic "orexigenic" peptides.

Changes in dietary macronutrient composition and/or central nervous system neuronal activity can underlie obesity and disturbed fuel homeostasis. We examined whether switching rats from a diet with high carbohydrate content (HC; i.e., regular chow) to diets with either high fat (HF) or high fat/high protein content at the expense of carbohydrates (LC-HF-HP) causes differential effects on body weight and glucose homeostasis that depend on the integrity of brain melanocortin (MC) signaling. In vehicle-treated rats, switching from HC to either HF or LC-HF-HP feeding caused similar reductions in food intake without alterations in body weight. A reduced caloric intake (-16% in HF and LC-HF-HP groups) required to maintain or increase body weight underlay these effects. Chronic third cerebroventricular infusion of the MC receptor antagonist SHU9119 (0.5 nmol/day) produced obesity and hyperphagia with an increased food efficiency again observed during HF (+19%) and LC-HF-HP (+33%) feeding. In this case, however, HF feeding exaggerated SHU9119-induced hyperphagia and weight gain relative to HC and LC-HF-HP feeding. Relative to vehicle-treated controls, SHU9119 treatment increased plasma insulin (2.8-4 fold), leptin (7.7-15 fold), and adiponectin levels (2.4-3.7 fold), but diet effects were only observed on plasma adiponectin (HC and LC-HF-HP<HF). Finally, SHU9119-treated LC-HF-HP-fed rats were less glucose tolerant than others. Relatively low plasma adiponectin levels likely contributed to this effect. Thus HF feeding amplifies obesity induced by impaired MC signaling, provided that the carbohydrate-to-protein (C/P) ratio is high enough. Reduction of the C/P ratio within a HF diet ameliorates hyperphagia and obesity in rats with impaired MC signaling but aggravates associated disturbances in fuel homeostasis.

Obesity has become a public health problem around the world. According to the Organisation for Economic Co-operation and Development (OECD, 2014 report), more than one in three adults in Mexico are obese. It is known that the hypothalamus, a region of the Central Nervous System (CNS), is actively involved in regulating energy homeostasis during obesity. Anatomically, the hypothalamus is composed of several nuclei coordinating body weight and metabolism, including the arcuate nucleus (ARC), which contains neurons co-expressing orexigenic peptides like Agouti-related protein (AgRP), Neuropeptide Y (NPY) and the anorexigenic peptide Pro-opiomelanocortin (POMC). During obesity, the integration and metabolic response in the ARC is disrupted by three molecular mechanisms: (1) activation of endoplasmic reticulum (ER) stress, (2) mitochondrial dysfunction, and (3) increase of ER and mitochondria contacts, known as Mitochondria-Associated Membranes (MAMs). In this context, it is proposed that MAMs formation induces mitochondrial Ca2+ overload and metabolic dysfunction, leading to insulin resistance and diabetes. Recently, MAMs formation has emerged as one of the molecular mechanisms underlying metabolic alterations during obesity. Thus, in this review we will focus on proposing scientific evidence to support the role of the MAMs and their function on calcium regulation during obesity, as an important pathological mechanism in the development of diabetes mellitus type 2.

Agouti-related protein (AgRP) is an orexigenic (appetite stimulating) neuropeptide suggested to exert tonic control over long-term energy balance. While some have speculated AgRP is not involved in the episodic (i.e. meal to meal energy intake) control, acute decreases in plasma agouti-related protein (AgRP) following a meal have been observed in humans in a role consistent with episodic control for AgRP. Whether changes in plasma AgRP are associated with episodic, and/or tonic changes in appetite has yet to be directly examined. The present study examined the relationship between agouti-related protein (AgRP), leptin and the regulation of appetite following a 48-h fast and an acute meal challenge. Blood samples were obtained from young lean and obese men before and after a 48 h fast (lean n = 10; obese n = 7). Fasting resulted in an increase in AgRP and a decrease in leptin with these changes being greater in lean than obese. In addition, blood samples were obtained from lean men before and 1, 2, 3 and 4 h after a meal (n = 8). Following a meal, AgRP was reduced from 2 to 4 h, a change that was dissociated from both leptin and subjective measures of hunger and satiety. These results demonstrate that AgRP is not associated with changes in hunger or satiety, and can change without corresponding changes in leptin. This suggests that AgRP may not be involved in the episodic control of appetite and the release of AgRP may involve signals other than leptin.

A regulated factor that contributes to maintenance of energy homeostasis is body weight and especially the size of its fat mass. Leptin as well as insulin are synthesized and secreted in proportion to body fat and each form a unique link between energy availability and CNS mechanisms that subserve the regulation of energy homeostasis. Both insulin and leptin affect signaling systems in the hypothalamus that involve a number of neuropeptides that serve a role in the regulation of food intake and energy expenditure. This chapter pays attention to to the interactions of leptin and insulin with hypopthalamic neuronal circuitry that contains neuropeptide Y (NPY), agouti-related peptide (AgRP) and proopiomelanocortin (POMC), and how these interactions affect appropriate changes in food intake and energy expenditure.

The effect of the fatty acid oxidation inhibitor, sodium mercaptoacetate (MA, 600 mumol/kg) on peripheral energy substrate metabolism was investigated in rats with permanent heart catheters. Rats were either fed, 48-h food deprived, or exercising for 30 min. Before and after intravenous MA injection, stress-free blood samples were taken for measurement of blood glucose, plasma free fatty acids (FFA), insulin, epinephrine (E), and norepinephrine (NE) concentrations. In fed animals, MA increased blood glucose, plasma FFA, and NE and decreased insulin concentrations. Plasma E levels did not change. In 48-h-deprived animals, MA elevated low baseline glucose concentrations to levels observed in MA-treated fed animals. Plasma insulin concentrations decreased to almost undetectable levels. Plasma catecholamines and FFA were increased compared to fed rats. In exercising rats, MA caused an exaggerated increase of blood glucose and a pronounced reduction of plasma insulin without affecting exercise-induced FFA and catecholamine responses. The data revealed that the mechanisms that regulate blood glucose concentrations during MA treatment are dependent on the nutritional state and ambient energy expenditure.

2-Deoxy-D-glucose (2DG) and 2-mercaptoacetate (MA) are drugs that competitively inhibit metabolism of glucose and fatty acids, respectively. Both 2DG and MA stimulate food intake. In addition, 2DG-induced glucoprivation is a known stimulus for adrenomedullary secretion. However, very little is known about the effects of MA on the sympathoadrenal system. In the present study, we examined effects of 2DG and MA on the activity of preganglionic neurons and the adrenal medulla, as indicated by expression of Fos-like immunoreactivity (Fos-li). 2DG, MA, or saline was administered using a stress-attenuated paradigm incorporating remote drug infusion. Expression of Fos-like immunoreactivity (Fos-li) was subsequently examined in the adrenal medulla and in preganglionic sympathetic neurons throughout the intermediolateral column (IML) of the thoracic and lumbar spinal cord. We found that 2DG increased Fos-li in the adrenal medulla and in the IML primarily at spinal cord segments T7-T10, where adrenomedullary preganglionic neurons reside. In contrast, MA did not induce Fos-li either in the adrenal medulla or in sympathetic preganglionic neurons at any cord level. Results support the hypothesis that decreased fatty acid oxidation is not a stimulus for adrenal medullary secretion and provide evidence for a highly selective stimulation of adrenal medullary preganglionic neurons by 2DG.

Exercise is known to increase hepatic glucose production. Previous studies have suggested that the sympathetic nerves only marginally contribute to this process. This study examined whether increased catecholamine response or increased adrenoceptor sensitivity might have affected previous results showing no effect of hepatic denervation on the increased hepatic glucose production during exercise. Hepatic sympathetic denervated rats, sham-operated rats and control rats were forced to swim against a counter current for 15 minutes. Denervations and sham operations were performed 9 days prior to swimming. The results show that denervation did not affect the changes in levels of blood glucose, plasma FFA, and catecholamines before, during and after swimming. Furthermore, hepatic adrenoceptor sensitivity was not altered in denervated rats, since intravenous infusions of epinephrine (20 ng/min) and norepinephrine (50 ng/min) similarly changed blood glucose and plasma FFA levels in liver-denervated, sham-operated and control rats. Thus, the increase in blood glucose levels during intravenous infusion of epinephrine and norepinephrine in the respective groups was 1.2 ± 0.3 and 1.0 ± 0.3 mmol/l (liver-denervated rats), 1.6 ± 0.4 and 0.7 ± 0.3 mmol/l (sham-operated rats) and 1.3 ± 0.3 and 0.8 ± 0.3 mmol/l (control rats), respectively. After adrenodemedullation, however, the rise of glucose levels during swimming in liver-denervated and control rats was completely abolished. Thus, the glucose response to swimming with and without adrenodemullation was 0.1 ± 0.4 and 1.7 ± 0.4 mmol/l in liver-denervated rats (P < 0.01) and −0.2 ± 0.4 and 2.2 ± 0.2 mmol/l in control rats (P < 0.001), respectively. The study therefore suggests that the peri-arterial hepatic nerves have a negligible influence on the glycemic response to exercise in rats. Instead, the glycemic response seems to be mediated mainly by the adrenal medulla.

The effects of glucoprivation and lipoprivation on sympathoadrenal outflow were investigated in rats with permanent intra-atrial catheters. Glucoprivation was induced by infusion of a hypoglycemic dose of insulin (3 U/kg) or by infusion of the glucose antimetabolite, 2-deoxy-D-glucose (2-DG, 200 mg/kg). Lipoprivation was induced by infusion of sodium mercaptoacetate (MA, 600 mumol/kg), which blocks beta oxidation of fatty acids. Stress-free blood samples for measurement of blood glucose, plasma nonesterified fatty acids (NEFA), and epinephrine (E) and norepinephrine (NE) concentrations were collected remotely before and after drug injection. Glucoprivation and lipoprivation differed significantly in their effects on the sympathoadrenal system. Both 2-DG- and insulin-induced glucoprivation appeared to increase adrenomedullary secretion selectively, leading to dramatically increased plasma E levels. Although plasma NE levels also rose during glucoprivation, other evidence suggests that this effect may be secondary to the rise in E. In contrast, MA-induced lipoprivation increased the outflow of NE from the sympathetic nerve endings without a significant effect on plasma E concentrations. Plasma E levels rose only late in the test, as blood glucose levels began to fall. Results indicate that glucoprivation and lipoprivation are distinct metabolic signals, each capable of selectively activating one branch of the sympathoadrenomedullary system and thereby facilitating the mobilization of metabolic fuels appropriate for the specific metabolic challenge.