van Gertjan Dijk

Agouti-related protein prevents self-starvation

Food restriction leads to a paradoxical increase in physical activity and further suppression of food intake, such as observed in anorexia nervosa.1,2 To understand this pathophysiological process, we induced physical hyperactivity and self-starvation in rats by restricting food in the presence of running wheels. Normally, decreased melanocortin receptor activity will prevent starvation.3,4 However, we found that self-starvation increased melanocortin receptors in the ventral medial hypothalamus, a brain region involved in eating behavior.5 Suppression of melanocortin receptor activity, via central infusion of Agouti-related protein (AgRP), increased survival rate in these rats by counteracting physical hyperactivity, food intake suppression as well as deregulated body temperature. We conclude that self-starvation may result from insufficient suppression of central melanocortin receptor activity.

Metabolic and behavioral responses to high-fat feeding in mice selectively bred for high wheel-running activity.

Objective:Increased dietary fat intake is a precipitating factor for the development of obesity and associated metabolic disturbances. Physically active individuals generally have a reduced risk of developing these unhealthy states, but the underlying mechanisms are poorly understood. In the present study, we investigated the effects of feeding a high-fat diet (HFD) on obesity development and fuel homeostasis in male and female mice with a trait for increased physical activity and in their controls.Methods:Male and female mice selectively bred for a high level of wheel running behavior over 30 generations and nonselected controls (background strain Hsd:ICR) were maintained on a standard lab chow high-carbohydrate diet (HCD) or on an HFD (60% fat). Food intake, body weight, indirect calorimetry parameters, spontaneous locomotor activity and several hormones relevant to metabolism and energy balance were measured.Results:On HFD, mice reduced food intake and increased body fat mass and plasma leptin levels, with the notable exception of the selected females, which increased their ingested calories without any effects on body mass or plasma leptin levels. In addition, they had an elevated daily energy expenditure (DEE), increased spontaneous cage activity (∼700% relative to controls) and higher resting metabolic rate (RMR) on the HFD compared with feeding the HCD. The selected males also had a higher DEE compared with controls, but no interaction with diet was observed. On HCD, adiponectin levels were higher in selected male, but not female, mice relative to controls. A marked increase in the level of plasma adiponectin was observed on the HFD in selected females, an effect of diet that was not observed in selected males.Conclusion:Genetically based high locomotor activity renders female, but not male, mice resistant to HFD-induced obesity by alterations in behavioral, endocrine and metabolic traits that facilitate fat utilization rather than limiting HFD intake.

Exercise and the regulation of energy intake

Energy balance is the resultant of ingested calories and energy expenditure and is generally maintained within narrow limits over prolonged periods. Exercise leads to an increase in energy expenditure which is, in the long-term, counteracted by increased energy intake. Evidence for this comes from a study in voluntarily running female rats that increased their daily food intake to 130% of the sedentary controls. In contrast, when considered on a short-term basis, exercise will suppress food intake to prevent a potentially dangerous disruption of energy substrate homeostasis. Studies in permanently cannulated rats submitted to a test meal and 2 hrs swimming reveal that both food intake and exercise lead to increases in glucose and free fatty acid (FFA) levels in the blood. These changes in glucose and FFA, combined with the exercise-induced alteration in among others glucagon, corticotropin releasing hormone (CRH) and body temperature, may lead to the short-term anorexic effect of exercise.

Influence of peri-arterial hepatic denervation on the glycemic response to exercise in rats

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Overfeeding, autonomic regulation and metabolic consequences.

SummaryThe autonomic nervous system plays an important role in the regulation of body processes in health and disease. Overfeeding and obesity (a disproportional increase of the fat mass of the body) are often accompanied by alterations in both sympathetic and parasympathetic autonomic functions. The overfeeding-induced changes in autonomic outflow occur with typical symptoms such as adiposity and hyperisulinemia. There might be a causal relationship between autonmic disturbances and the consequences of overfeeding and obesity. Therefore studies were designed to investigate autonomic functioning in experimentally and genetically hyperphagic rats. Special emphasis was given to the processes that are involved in the regulation of peripheral energy substrate horneostasis. The data revealed that overfeeding is accompanied by increased parasympathetic outflow. Typical indices of vagal activity (such as the cephalic insulin release during food ingestion) were increased in all our rat models for hyperphagia. Overfeeding was also accompanied by increased sympathetic tone, reflected by enhanced baseline plasma norepinephrine (NE) levels in both VMH-lesioned animals and rats rendered obese by hyperalimentation. Plasma levels of NE during exercise were, however, reduced in these two groups of animals. This diminished increase in the exercise-induced NE outflow could be normalized by prior food deprivation. It was concluded from these experiments that overfeeding is associated with increased parasympathetic and sympathetic tone. In models for hyperphagia that display a continuously elevated nutrient intake such as the VMH-lesioned and the overfed rat, this increased sympathetic tone was accompanied by a diminished NE response to exercise. This attenuated outflow of NE was directly related to the size of the fat reserves, indicating that the feedback mechanism from the periphery to the central nervous system is altered in the overfed state.

Gestational weight gain by reduced brain melanocortin activity affects offspring energy balance in rats

Introduction:Excessive gestational body weight gain of mothers may predispose offspring towards obesity and metabolic derangements. It is difficult to discern the effects of maternal obesogenic factors—such as diet and/or thrifty genetic predisposition—from gestational weight gain per se.Methods:For this reason, genetically normal Wistar rats that were fed regular chow were rendered hypothalamically obese by chronic third-cerebral ventricular (i3vt) infusion during pregnancy and lactation with the melanocortin-3,4 receptor blocker SHU9119. This procedure caused significant increases in body weight gain during pregnancy and lactation compared with controls, and the effects thereof on offspring energy balance and fuel homeostasis were investigated.Results:At birth, litter weight and size, but not individual pup weight, of SHU9119-treated mothers were significantly smaller than controls. In litters culled to eight, pup weight gain during lactation was only transiently increased by treatment. After weaning, however, male offspring of SHU9119-treated mothers became increasingly heavier over time relative to controls until killing at 9 months. This effect was only transient in females. Increased body weights of males were not associated with disturbances in glucose homeostasis, but with increased energy expenditure instead. Multiple regression analysis revealed that gestational body weight gain, irrespective of the group, contributed positively to increased visceral fat deposition and carbohydrate oxidation in the male offspring. In contrast, the pre-pregnancy body weight of mothers contributed positively to male offspring daily energy expenditure, subcutaneous fat and eviscerated carcass as well as structural organ weights. In female offspring, gestational body weight gain, but not pre-gestational body weight, contributed both to aspects of weight gain as well as to the shift of fat oxidation toward carbohydrate oxidation.Conclusion:Gestational weight gain induced by low brain melanocortin receptor activity can lead to increased body weight gain in the offspring (particularly in males) independent of obesogenic dietary and/or thrifty genetic predisposition.

Effects of selective breeding for increased wheel-running behavior on circadian timing of substrate oxidation and ingestive behavior

Fluctuations in substrate preference and utilization across the circadian cycle may be influenced by the degree of physical activity and nutritional status. In the present study, we assessed these relationships in control mice and in mice from a line selectively bred for high voluntary wheel-running behavior, either when feeding a carbohydrate-rich/low-fat (LF) or a high-fat (HF) diet. Housed without wheels, selected mice, and in particular the females, exhibited higher cage activity than their non-selected controls during the dark phase and at the onset of the light phase, irrespective of diet. This was associated with increases in energy expenditure in both sexes of the selection line. In selected males, carbohydrate oxidation appeared to be increased compared to controls. In contrast, selected females had profound increases in fat oxidation above the levels in control females to cover the increased energy expenditure during the dark phase. This is remarkable in light of the finding that the selected mice, and in particular the females showed higher preference for the LF diet relative to controls. It is likely that hormonal and/or metabolic signals increase carbohydrate preference in the selected females, which may serve optimal maintenance of cellular metabolism in the presence of augmented fat oxidation.

Behavioral Genetics of the Mouse Volume II

Eating disorders frequently develop during adolescence or early adulthood. Much attention is paid to anorexia nervosa (AN) and bulimia nervosa (BN), both eating disorders that are more likely to be found in females than in males (Hoek, 2006). As of now, it is estimated that AN and BN affect about 3% of young women with nearly twice this number having eating problems that do not reach diagnostic thresholds. Consequences of these eating disorders can be devastating and far-reaching. For example, individuals suffering from AN or BN frequently go into remission, and about 5 to 10% of them die due to complications such as heart and kidney failure (Casiero and Frishman, 2006; Hoek, 2006). According to the DSM-IV criteria, AN is characterized by self-starvation, and a refusal to maintain a minimally normal body weight. Bulimia nervosa is characterized by repeated binge-eating episodes, which are usually followed by self-induced vomiting, intake of laxatives and diuretics, or other medications aimed at induction of weight loss. Eating disorders are frequently found to occur with other psychiatric disorders such as depression, addiction, and anxiety. Furthermore, individuals suffering from AN and BN often have a disturbed perception of body shape and weight, and judge themselves as too fat (Ruuska et al., 2005). Another frequently mentioned eating disorder on the other side of the spectrum is binge eating disorder (BED). According to the DSM-IV criteria, BED subjects have binges at least twice a week over a period of six months or more. Each binge is characterized by ingesting a large amount of food at a high feeding rate, and continues far beyond the normal sensation of satiety. Binge eating disorder is commonly associated with obesity, and - as opposed to AN and BN subjects - BED obese individuals are generally quite aware of their fat state (Gromel et al., 2000). In fact, they frequently feel stigmatized as such (Puhl et al., 2007). Since obesity is considered a general medical condition according to the International Classification of Diseases (ICD), and no consistent psychological syndrome is associated with it, it has not been classified in the DSM-IV. However, reports nevertheless suggest that obese individuals already at adolescence are frequently depressed according to the DSM-IV criteria (McElroy et al., 2004; Sjoberg et al., 2005).

The metabolic effects of olanzapine and topiramate in rats and humans

In humans the anti-psychotic Olanzapine (OLZ) has negative side effects on metabolism: it causes weight gain and increases the risk of developing type 2 Diabetes. The anti-convulsant Topiramate (TPM) has the opposite effects: it reduces body weight and improves insulin sensitivity. Because of this, it has been proposed to use TPM to counteract OLZs side effects. The underlying mechanisms by which OLZ and TPM influence metabolism are unknown. To study this, we performed a series of studies in both rats and humans. In rats we administered OLZ and TPM via a permanent intragastric cannula, to mimic oral drug administration, and found that chronic OLZ treatment stimulates weight gain and causes insulin resistance reflected by increased insulin responses during an intravenous-glucose tolerance test OLZ also decreased locomotor activity and core temperature, pointing to a reduction in energy expenditure. OLZ also increased weight gain in humans, accompanied with decreased daily physical activity, reduced body temperature and increased baseline and glucosestimulated insulin levels during an oral glucose tolerance test. TPM reduced the OLZ-induced overeating and weight gain in both rats and humans combined with an increased postprandial satiety rating (in humans). We conclude that, in both rats and humans, a reduction in energy expenditure may explain, at least in part, the OLZ effects on weight gain and that the OLZ-induced effects on insulin resistance has a peripheral side of action. We also conclude that TPM may prevent the negative metabolic side effects induced by OLZ. Supported by: Top Institute Pharma.