B. Balkan

Neuroendocrine Mechanisms Involved in Regulation of Body Weight, Food Intake and Metabolism

Body weight regulation is the result of food intake and energy expenditure. The central nervous system (CNS), and in particular, the hypothalamus, controls food intake as well as metabolism, the latter mainly by autonomic effects on the islet of Langerhans, hepatocytes and adipocytes. Body weight, more precisely body fat content, is probably controlled by a feedback mechanism in which insulin, released from the B cell of the islet of Langerhans, plays a key role. The islet of Langerhans is an intricate neuroendocrine unit in which the release of glucagon, insulin, and somatostatin from A, B, and D cells, respectively, is controlled by the CNS via a rich autonomic innervation. In addition, the endocrine cells of the pancreas influence each other by paracrine actions. The CNS control of the islets shapes the plasma insulin and blood glucose profiles during the circadian cycle and thereby regulates the nutrient flow to the different tissues in the body. Thus, the CNS structures involved in regulation of body weight and food intake control also metabolism. The mechanisms contributing to match food intake and the needs of metabolism are discussed.

Hepatic-Portal and Cardiac Infusion of CCK-8 and Glucagon Induce Different Effects on Feeding

In order to compare effects of circulating CCK-8 and glucagon on food intake, rats were provided with a permanently implanted catheter in the right atrium. Another cannula was implanted into the hepatic-portal vein by a new technique. After a standard fasting period graded loads of CCK-8 and glucagon were infused via these catheters during refeeding. Intracardiac glucagon and CCK loads dose-dependently suppressed meal size. Intraportal infusion of glucagon caused similar suppression compared to intracardiac administration. This may indicate a minor role of the liver as a target for the suppression of feeding by glucagon. In contrast, intraportal infusion of CCK-8 did not reduce food intake. The results indicate that CCK-8 is removed or inactivated by the liver. It is suggested that CCK-8 acts locally on vagal nerve endings to exert its suppressive action on food intake.

Sympathoadrenal Function in Genetically Obese Zucker Rats

The effects of genetic obesity on the actions and alterations of the sympathetic nervous system were studied in 10-12-month-old obese (fa/fa) and lean (Fa/-) Zucker rats. Blood glucose, plasma insulin, epinephrine (E), norepinephrine (NE), and free fatty acids (FFA) concentrations were measured in blood samples taken through a permanent heart catheter before, during, and after exercise or intravenous infusion of E and NE. Baseline plasma FFA and insulin levels were markedly increased in the obese animals. Exercise, i.e., strenuous swimming against a counter current for 15 min, led to reduction of plasma insulin concentrations and an increase of all other blood components in lean Zucker rats. In obese animals, an exaggerated increase of blood glucose and a large suppression of plasma insulin occurred. Plasma FFA levels tended to decline during exercise. Plasma catecholamine patterns in the exercising fatty Zuckers were not different to those of the lean animals. Infusion of E caused an increase of blood glucose and a decrease of plasma insulin concentrations in both groups of animals. The increase in blood glucose in the obese animals was significantly larger compared to the changes in the lean animals. Infusion of NE significantly reduced plasma insulin concentration in obese but not in lean animals. The results revealed that activation of the sympathetic system, expressed as exercise-induced alterations in plasma E and NE levels, is normal in obese Zucker rats. However, postsynaptic receptor effects of catecholamines on glycogenolysis and lipolysis are different in obese and lean animals, which points to permanent changes in adrenoceptor mechanisms on adipocytes, hepatocytes, and muscle cells in obesity.

Hyperinsulinemia and Glucose Tolerance in Obese Rats With Lesions of the Ventromedial Hypothalamus: Dependence on Food Intake and Route of Administration

This study was performed to investigate the consequences of developing obesity on glucose homeostasis in animals showing hyperphagia plus vagal hyperinsulinemia and rats that were normophagic and hyperinsulinemic. Male rats were lesioned in the ventromedial hypothalamus (VMH) and kept either under ad libitum or absolute (oral or intragastrical) pair-feeding conditions for 4 weeks. Hyperphagic rats, as well as normophagic VMH rats, became obese, but only ad lib-fed obese rats displayed glucose intolerance to intravenous (IV) glucose infusions. Orally pair-fed VMH rats also showed normal oral and intragastric glucose tolerance, but in intragastrically fed VMH animals and controls, oral and intragastric glucose tolerance was decreased. These results indicate that (1) obesity as a consequence of VMH lesions is not dependent on hyperphagia, confirming earlier reports, and also independent of the ingestion of bulk meals. (2) beta-cell release of insulin to IV glucose infusion is not sufficient when hyperphagia and vagally mediated hyperinsulinemia coincide, and is therefore dependent on several factors; and (3) oral glucose intolerance develops when preabsorptive reflexes are blunted, irrespective of whether the animals were hyperinsulinemic or not.

Neuroendocrine Factors Regulating Blood Glucose, Plasma FFA and Insulin in the Development of Obesity

A number of neurotransmitters and neuropeptides in the hypothalamus play a role in the control of food intake, metabolism, and body weight. Particularly, noradrenergic mechanisms in several areas of the hypothalamus are involved. Control of peripheral metabolism by the hypothalamus is achieved via autonomic modulation of the function of hepatocytes, adipocytes, and the endocrine cells in the islets of Langerhans. The autonomic control mechanisms ultimately lead to an appropriate shaping of blood glucose, plasma FFA, and insulin profiles to guarantee an adequate flow of nutrients under different physiological situations. Peripheral insulin and glucose can penetrate into the brain where they might affect the function of those brain structures involved in control of food intake, metabolism, and body weight.

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)

BIPHASIC INSULIN-SECRETION AFTER INTRAVENOUS BUT NOT AFTER INTRAPORTAL CCK-8 INFUSION IN RATS

The effects of physiological doses of sulfated cholecystokinin-8 (CCK-8) on insulin secretion were investigated in unrestrained unanesthetized rats. The routes of administration were intravenous or intraportal infusion. Intravenous infusion (0.33–5.0 μg CCK-8 · kg−1 · 20 min−1) resulted in a biphasic response pattern consisting of a fast 1st-min rise in plasma insulin concentration and a slower second phase that lasted throughout the infusion. The first phase showed the same amplitude with all amounts of CCK-8 administered in this study, whereas the second phase exhibited dose dependency. Blood glucose levels were lowered during all infusions of CCK-8, although the second phase of insulin release was absent with the lowest dose. These results suggest a strong stimulatory effect of CCK-8 on the pancreatic β-cells, probably by changing the set point for glucose. The described effects of intravenous administration of CCK-8 cannot be produced when the infusion is given into the portal vein. Only very high concentrations of CCK-8 (15 μg · kg−1 · 20 min−1) produced a small increase in plasma insulin levels, indicating a strong CCK-8-eliminating mechanism in the liver. These results indicate that 1) CCK-8 evokes biphasic insulin release and a concomitant drop in glucose levels, and 2) CCK-8 acting on the β-cell in vivo is not of intestinal origin but is probably released by the pancreatic vagai branch.

Overfeeding-Induced Obesity in Rats : Insulin Sensitivity and Autonomic Regulation of Metabolism

The metabolic consequences of the development of obesity and the underlying mechanisms were investigated. For this purpose, male rats were overfed for 5 weeks through long-term gastric catheters. Permanent cardiac cannulas implanted before the overfeeding period allowed frequent blood sampling and infusions without disturbing the rats. Hyperalimented rats became grossly obese, displayed elevated basal plasma norepinephrine (NE) concentrations, and developed hyperinsulinemia and insulin insensitivity, but remained normoglycemic and preserved normal intravenous (IV) glucose tolerance. During physical exercise (ie, 15 minutes of swimming), obese rats displayed exaggerated increases in blood glucose concentrations, whereas plasma free fatty acid (FFA) responses were blunted. These alterations were probably due to decreased NE release by the sympathetic nervous system during exercise and to altered tissue responsivity to adrenergic stimulation. The latter was demonstrated by infusions of catecholamines in the resting state. Responses to mild stress were increased in obese animals, as indicated by increased responses of plasma epinephrine (E) and corticosterone during handling and first contact with water. The results of the present study indicate that overfeeding induces changes in the sympathetic control of metabolism and insulin secretion. Whereas elevated NE levels in the basal state probably reflect increased energy expenditure, the pattern of nutrient mobilization during exercise is directed toward sparing of fats.

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.

Cardiac and behavioral responses of long-term obese and lean Zucker rats to emotional stress

Obesity is known as a risk factor in stress-related cardiovascular pathology in man. The length of obesity can be an important interacting variable. Therefore, cardiac and behavioral responses to emotional stress were studied in 1-year-old, genetically obese (fa/fa) and lean(Fa/-) male Zucker rats, a frequently used animal of genetic obesity. An early bradycardic response to emotional stress evoked by stimuli associated with brief previous inescapable foot shock, as observed in lean rats, was absent in the fatty Zuckers. This difference was not due to a learning deficit: obese and lean Zuckers showed the same degree of conditioned behavioral responses to the emotional stress. Furthermore, the magnitude of the novelty induced behavioral arousal was also comparable. As far as the regulation of body temperature is concerned, the fa/fa rats displayed a diminished increment in rectal temperature in response to the emotional stress. In conclusion, the results showed an impairment of phasic change in the parasympathetic drive of heart to emotional stress in the long-term obese animals. The diminished activation of heat production points to a blunted response of certain branches of the sympathetic nervous system to emotional stress. The findings favor the hypothesis that dysfunction of cardiac vagal drive in relation to stress is of pathologic importance in long-term obesity.