Gertjan van Dijk

Melanocortin receptors in leptin effects

Leptin acts on the central nervous system to cause a reduction in food intake and body weight,. The melanocortin system in the brain is also implicated in energy homeostasis, with agonists of the melanocortin-4 (MC4) receptor reducing food intake and targeted mutation of the MC4 receptor causing obesity. We now show that MC4 receptor signalling is an important mediator of leptins effects on food intake and body weight, demonstrating a link between the two systems.

The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives

Summary Mammals expend energy in many ways, including basic cellular maintenance and repair, digestion, thermoregulation, locomotion, growth and reproduction. These processes can vary tremendously among species and individuals, potentially leading to large variation in daily energy expenditure (DEE). Locomotor energy costs can be substantial for large-bodied species and those with high-activity lifestyles. For humans in industrialized societies, locomotion necessary for daily activities is often relatively low, so it has been presumed that activity energy expenditure and DEE are lower than in our ancestors. Whether this is true and has contributed to a rise in obesity is controversial. In humans, much attention has centered on spontaneous physical activity (SPA) or non-exercise activity thermogenesis (NEAT), the latter sometimes defined so broadly as to include all energy expended due to activity, exclusive of volitional exercise. Given that most people in Western societies engage in little voluntary exercise, increasing NEAT may be an effective way to maintain DEE and combat overweight and obesity. One way to promote NEAT is to decrease the amount of time spent on sedentary behaviours (e.g. watching television). The effects of voluntary exercise on other components of physical activity are highly variable in humans, partly as a function of age, and have rarely been studied in rodents. However, most rodent studies indicate that food consumption increases in the presence of wheels; therefore, other aspects of physical activity are not reduced enough to compensate for the energetic cost of wheel running. Most rodent studies also show negative effects of wheel access on body fat, especially in males. Sedentary behaviours per se have not been studied in rodents in relation to obesity. Several lines of evidence demonstrate the important role of dopamine, in addition to other neural signaling networks (e.g. the endocannabinoid system), in the control of voluntary exercise. A largely separate literature points to a key role for orexins in SPA and NEAT. Brain reward centers are involved in both types of physical activities and eating behaviours, likely leading to complex interactions. Moreover, voluntary exercise and, possibly, eating can be addictive. A growing body of research considers the relationships between personality traits and physical activity, appetite, obesity and other aspects of physical and mental health. Future studies should explore the neurobiology, endocrinology and genetics of physical activity and sedentary behaviour by examining key brain areas, neurotransmitters and hormones involved in motivation, reward and/or the regulation of energy balance.

Inflammation and NF-κB in Alzheimer's Disease and Diabetes

Inflammatory processes are a hallmark of many chronic diseases including Alzheimers disease and diabetes mellitus. Fairly recent statistical evidence indicating that type 2 diabetes increases the risk of developing Alzheimers disease has led to investigations of the potential common processes that could explain this relation. Here, we review the literature on how inflammation and the inducible nuclear factor NF-kappaB might be involved in both diabetes mellitus and Alzheimers disease and whether these factors can link both diseases.

Behavioral and physiological responses to stress are affected by high-fat feeding in male rats

Interactions between monoaminergic neurochemistry and macronutrient intake have been frequently shown. Because monoaminergic systems in the brain are also closely involved in behavioral and physiological stress responses it can be hypothesized that differences in the macronutrient composition of diets are reflected in these responses. The present studies, therefore, were designed to assess the consequences of a change in dietary macronutrient composition on a variety of physiological and behavioral responses (both acute and long-term) to a number of stressors. The effect of chronic high-fat (HF; 61% kcal from fat) feeding on the stress responses was compared with controls receiving regular high-carbohydrate (HC; 63% kcal from carbohydrates) laboratory chow. Rats were kept on this diet for at least 2 months before they were exposed to either psychological (social defeat) or physiological (lipopolysaccharide, LPS, administration) stress. At baseline, chronic HF feeding caused a slight, but significantly reduction in body temperature relative to that observed in HC-fed rats. Following social defeat or LPS injection, HF feeding caused a faster recovery of the body temperature increase relative to animals on the HC diet. Stress-induced suppression of home cage locomotor activity and body weight gain were also reduced by HF feeding. The serotonergic 5-HT(1a) receptor hyposensitivity that was observed in HC-fed rats 2 weeks after stress was absent in the HF regimen. Although the present results cannot be readily interpreted as showing purely beneficial effects of high-fat diets on stress responsivity, the findings in the present study do encourage further investigation of possible ameliorating effects of high-fat diets on aspects of the behavioral and physiological response stress.

Inflammation and NF-kappa B in Alzheimer's Disease and Diabetes

Inflammatory processes are a hallmark of many chronic diseases including Alzheimers disease and diabetes mellitus. Fairly recent statistical evidence indicating that type 2 diabetes increases the risk of developing Alzheimers disease has led to investigations of the potential common processes that could explain this relation. Here, we review the literature on how inflammation and the inducible nuclear factor NF-kappaB might be involved in both diabetes mellitus and Alzheimers disease and whether these factors can link both diseases.

Central infusion of glucagon-like peptide-1-(7-36) amide (GLP-1) receptor antagonist attenuates lithium chloride-induced c-Fos induction in rat brainstem

Central infusion of glucagon-like peptide-1-(7-36) amide (GLP-1) and intraperitoneal (i.p.) injection of lithium chloride (LiCl) produce similar patterns of c-Fos induction in the rat brain. These similarities led us to assess the hypothesis that neuronal activity caused by i.p. injection of LiCl involves activation of central GLP-1 pathways. We therefore determined if third-ventricular (i3vt) infusion of a GLP-1 receptor antagonist would block LiCl-induced c-Fos expression in the brainstem. Relative to rats pretreated with i3vt infusion of vehicle, pretreatment with the potent GLP-1 receptor antagonist, des His1 Glu9 exendin-4 (10.0 microgram), significantly attenuated LiCl-induced (76 mg/kg; i.p.) c-Fos expression in several brainstem regions, including the area postrema, the nucleus of the solitary tract, and the lateral parabrachial nucleus. While central infusion of des His1 Glu9 exendin-4 also blocked GLP-1-induced (10.0 microgram) anorexia and c-Fos expression, the antagonist produced no independent effects on food intake or c-Fos expression. These results suggest that LiCl-induced c-Fos expression in the rat brainstem is mediated, at least in part, by GLP-1 receptor signaling.

The Role of Leptin in the Regulation of Energy Balance and Adiposity

Since its discovery, leptin (a 167‐amino acid product of the OB gene) has quickly moved to the forefront as an important hormone for regulation of energy balance. It closes a feedback loop from adipose tissue to hypothalamic neuropeptide‐containing neural circuitry involved in regulation of food intake and neuroendocrine/autonomic outflow. While increased central leptin signalling reduces adiposity via a reduction in food intake, it also has remarkable metabolic effects that promote leanness, independent of food intake. These include: (i) increased energy expenditure, (ii) in‐place degradation of fat, and (iii) increased thermogenesis. Hypothalamic neurones that synthesize corticotropin releasing hormone and melanocortins (i.e. α‐melanocyte‐stimulating hormone and agouti‐related protein) are likely effector pathways that mediate the anorexigenic and metabolic effects of leptin. Activation of sympathetic outflow (via neuropeptidergic effector pathways of central leptin) to a number of tissues that store fat might be an important mechanism through which these peripheral metabolic effects are elicited. It is proposed that these peripheral metabolic effects contribute to the satiating properties of leptin.

Central leptin stimulates corticosterone secretion at the onset of the dark phase

Leptin, a hormone secreted by adipose tissue in proportion to body adiposity, is proposed to be involved in the central nervous regulation of food intake and body weight. In addition, evidence is emerging that leptin regulates neuroendocrine and metabolic functions as well, presumably via its action in the central nervous system (CNS). To investigate this regulatory effect of leptin, we infused 3.5 μg of human leptin directly into the third cerebral ventricle (i3vt) of lean male Long-Evans rats, 90 min before the onset of their dark phase. Before and after infusion, blood samples were withdrawn through indwelling catheters for assessment of hormonal (plasma corticosterone, insulin, leptin), autonomic (plasma norepinephrine, epinephrine), and metabolic (plasma glucose) parameters. 13vt leptin caused an increase in plasma corticosterone and plasma leptin levels relative to the control condition. The effects of i3vt leptin on corticosterone secretion became particularly apparent after the onset of the dark phase. The results of the present study indicate that i3vt leptin stimulates the hypothalamo-pituitary-adrenal (HPA) axis, particularly when rats normally encounter their largest meals. These results are consistent with the possibility that high circulating leptin levels may underlie the increased activity of the HPA axis that is generally characteristic of human obesity and most animal models of obesity.

Hormonal and metabolic effects of paraventricular hypothalamic administration of neuropeptide Y during rest and feeding

To investigate the role of neuropeptide Y (NPY) in the paraventricular nucleus of the hypothalamus (PVN) in the regulation of autonomic outflow, hormonal (plasma insulin and catecholamines), metabolic (blood glucose and plasma free fatty acids) and cardiovascular (heart rate and main arterial pressure) indices were measured before, during, and after bilateral infusion of NPY (1.0, 0.2, 0.04 micrograms in 1 microliter synthetic CSF) into the PVN of conscious resting rats. Administration of the highest dose (1.0 microgram/microliter) caused bradycardia and reduced circulating norepinephrine levels without effecting circulating fuels, insulin or epinephrine. In a second experiment, feeding-induced changes in hormonal and metabolic indices were assessed after NPY administration (1.0 microgram/microliter) into the PVN. During and after feeding, NPY enhanced the feeding-induced insulin response (P < 0.01) and attenuated the feeding-induced norepinephrine response (P < 0.05). The results of the present study suggest that stimulation of NPY receptors in the PVN decreases sympathetic activity and increases parasympathetic activity in resting conditions, and that these effects are potentiated during feeding.

METABOLIC, GASTROINTESTINAL, AND CNS NEUROPEPTIDE EFFECTS OF BRAIN LEPTIN ADMINISTRATION IN THE RAT

To investigate whether brain leptin involves neuropeptidergic pathways influencing ingestion, metabolism, and gastrointestinal functioning, leptin (3.5 μg) was infused daily into the third cerebral ventricular of rats for 3 days. To distinguish between direct leptin effects and those secondary to leptin-induced anorexia, we studied vehicle-infused rats with food available ad libitum and those that were pair-fed to leptin-treated animals. Although body weight was comparably reduced (-8%) and plasma glycerol was comparably increased (142 and 17%, respectively) in leptin-treated and pair-fed animals relative to controls, increases in plasma fatty acids and ketones were only detected (132 and 234%, respectively) in pair-fed rats. Resting energy expenditure (-15%) and gastrointestinal fill (-50%) were reduced by pair-feeding relative to the ad libitum group, but they were not reduced by leptin treatment. Relative to controls, leptin increased hypothalamic mRNA for corticotropin-releasing hormone (CRH; 61%) and for proopiomelanocortin (POMC; 31%) but did not reduce mRNA for neuropeptide Y. These results suggest that CNS leptin prevents metabolic/gastrointestinal responses to caloric restriction by activating hypothalamic CRH- and POMC-containing pathways and raise the possibility that these peripheral responses to CNS leptin administration contribute to leptins anorexigenic action.To investigate whether brain leptin involves neuropeptidergic pathways influencing ingestion, metabolism, and gastrointestinal functioning, leptin (3.5 micrograms) was infused daily into the third cerebral ventricular of rats for 3 days. To distinguish between direct leptin effects and those secondary to leptin-induced anorexia, we studied vehicle-infused rats with food available ad libitum and those that were pair-fed to leptin-treated animals. Although body weight was comparably reduced (-8%) and plasma glycerol was comparably increased (142 and 17%, respectively) in leptin-treated and pair-fed animals relative to controls, increases in plasma fatty acids and ketones were only detected (132 and 234%, respectively) in pair-fed rats. Resting energy expenditure (-15%) and gastrointestinal fill (-50%) were reduced by pair-feeding relative to the ad libitum group, but they were not reduced by leptin treatment. Relative to controls, leptin increased hypothalamic mRNA for corticotropin-releasing hormone (CRH; 61%) and for proopiomelanocortin (POMC; 31%) but did not reduce mRNA for neuropeptide Y. These results suggest that CNS leptin prevents metabolic/gastrointestinal responses to caloric restriction by activating hypothalamic CRH- and POMC-containing pathways and raise the possibility that these peripheral responses to CNS leptin administration contribute to leptins anorexigenic action.