Robert C. Ritter

Gastrointestinal mechanisms of satiation for food

Satiation for food comprises the physiological processes that result in the termination of eating. Satiation is evoked by physical and chemical qualities of ingested food, which trigger afferent signals to the brain from multiple sites in the GI tract, including the stomach, the proximal small intestine, the distal small intestine and the colon. The physiological nature of each signals contribution to satiation and overall control of food intake is likely to vary, depending on the level of the GI tract from which the signal arises. This article is a critical, though non-exhaustive, review of our current understanding of the mechanisms and adaptive value of satiation signals from the stomach and intestine.

Capsaicin application to central or peripheral vagal fibers attenuates CCK satiety

Capsaicin treatment destroys small primary sensory neurons including a subpopulation of vagal afferents. Intraperitoneal, fourth ventricular or perivagal application of capsaicin attenuated or abolished cholecystokinin (CCK)-induced suppression of food intake. Capsaicin applied to the thoracolumbar spinal cord or to the pyloric region of the stomach did not alter CCK-induced reductions of food intake. Intraperitoneal capsaicin treatment reduced substance P-like immunoreactivity (SPLI) in the spinal dorsal horn and parts of the dorsal hindbrain. SPLI depletion, therefore, served as a histochemical indicator of the spread of capsaicin from its site of application. Capsaicin applied directly to the vagal trunks did not reduce SPLI in the spinal cord or hindbrain. Intraventricular capsaicin reduced SPLI in the hindbrain but not in the spinal cord. These data indicate that localized capsaicin application attenuates CCK-induced suppression of food intake by impairing the function of either central or peripheral portions of vagal afferent neurons. The data also support the conclusion that intraperitoneal capsaicin attenuates CCK-induced suppression of feeding by impairing vagal sensory function.

Ablation of the area postrema causes exaggerated consumption of preferred foods in the rat

The area postrema (AP) is a hindbrain circumventricular organ (CVO) with apparent chemoreceptive function. The AP has demonstrated neural and vascular connections with the nucleus of the solitary tract (SOL), a structure which receives the primary visceral afferents from the oral cavity and gastrointestinal tract. The anatomical structure and connections of the AP suggests a potential role for this CVO in the control of feeding behavior. We have found that rats with surgically produced AP lesions consumed the same amounts of pelleted food ad libitum as control rats. Lesioned and control rats also consumed equal amounts of lab chow after 21 h food deprivation. However, when presented with a preferred food (instant breakfast or cookies), AP-lesioned rats consumed at least double the amount consumed by control rats. It is possible that AP lesions impair sensitivity to satiety cues. However, lesion rats did decrease their instant breakfast intake in response to cholecystokinin injections or gastric preloads. Furthermore, overingestion by AP-lesioned rats occurred only in response to preferred (highly palatable) foods and not in response to lab chow. Lesioned rats rejected quinine-adulterated instant breakfast at the same adulterant concentration as controls. Therefore, the lesioned rats do not suffer from ageusia or from enhanced responsiveness to bitter taste. Rather, the selective overeating by AP-lesioned rats may reflect an enhanced behavioral response to the sensory qualities of normally preferred foods. The close association of the AP with the SOL provides a neuroanatomical avenue by which a putative AP-chemoreceptor could alter the quality or intensity of information arriving via the taste afferents. Such tuning of gustatory mechanisms could be an important component of ingestive control.

RATS MAINTAINED ON HIGH-FAT DIETS EXHIBIT REDUCED SATIETY IN RESPONSE TO CCK AND BOMBESIN

Rats maintained on high-fat diets often exhibit increased food intake and weight gain. We hypothesized that high-fat diets might result in reduced sensitivity to hormonal signals responsible for terminating food intake--satiety signals. The intestinal hormone cholecystokinin (CCK) and the gastrointestinal neuropeptide, bombesin (BBS) both have been proposed as satiety signals. To determine whether maintenance on high-fat diets alters sensitivity to satiating effects of CCK and bombesin (BBS), rats were maintained on a low fat diet (LF), a high-fat diet that was isocaloric with the low-fat diet (HF), or one of two hypercaloric high-fat diets (HF-1, HF-2) that differed from HF and LF in fat, fiber, and total caloric content. CCK and bombesin reduced food intake significantly less in rats maintained on high-fat diets, compared to those on the low fat diet. Neither high caloric intake, which was associated with increased body weight gain on the two hypercaloric diets, nor fiber content of the diet accounted for the reduced response of HF rats to CCK. Rather, reduced sensitivity to CCK was related only to the high proportion of calories taken as fat. We also determined whether reduced CCK sensitivity was due to the maintenance on a particular diet or to the diet eaten during a CCK test. After CCK, rats maintained on LF reduced food intake more (49%) than rats maintained on HF (22%), regardless of whether they ate HF or LF during the CCK test itself. These findings indicate that maintenance of rats on high-fat diets reduces sensitivity to some peptide satiety signals. Reduced sensitivity to satiety signals might contribute to overeating and obesity often observed when rats are maintained on high-fat diets.

Long-term CCK-leptin synergy suggests a role for CCK in the regulation of body weight

The gut peptide CCK is a nutrient-related signal important to the control of food intake. In the present studies, we observed that a single intraperitoneal injection of CCK (1-2 μg/kg) given 2-3 h after intracerebroventricular leptin (2-5 μg) reduced body weight and chow intake over the ensuing 48 h more than did leptin alone. CCK alone had no effect on either 48-h chow intake or body weight but significantly reduced feeding during a 30-min sucrose test. However, reduction of 30-min sucrose intake by CCK was not enhanced by prior intracerebroventricular leptin. The present data suggest that CCK can contribute to the regulation of body weight when central leptin levels are elevated.The gut peptide CCK is a nutrient-related signal important to the control of food intake. In the present studies, we observed that a single intraperitoneal injection of CCK (1-2 microgram/kg) given 2-3 h after intracerebroventricular leptin (2-5 microgram) reduced body weight and chow intake over the ensuing 48 h more than did leptin alone. CCK alone had no effect on either 48-h chow intake or body weight but significantly reduced feeding during a 30-min sucrose test. However, reduction of 30-min sucrose intake by CCK was not enhanced by prior intracerebroventricular leptin. The present data suggest that CCK can contribute to the regulation of body weight when central leptin levels are elevated.

Cholecystokinin: proofs and prospects for involvement in control of food intake and body weight

Evidence that CCK participates in the control of meal size is compelling, but the avenues by which CCK may affect daily food intake and body weight regulation are still uncertain. Although participation of brain CCK in control of food intake is acknowledged, our focus here is on participation of peripheral CCK in the control of food intake. Therefore, in this article we (1) review evidence for CCKs participation in control of meal size, (2) document involvement of CCK-A receptors located on vagal sensory neurons in control of food intake by exogenous and endogenous CCK, (3) point out apparent discrepancies in the experimental record, which auger for non-endocrine sources of CCK and non-vagal sites of CCK action, and (4) summarize recent observations, suggesting mechanisms by which CCK could participate in the control of daily food intake and body weight regulation.

Modulation of vagal afferent excitation and reduction of food intake by leptin and cholecystokinin

The gut-peptide, cholecystokinin (CCK), reduces food intake by acting at CCK-1 receptors on vagal afferent neurons, whereas the feeding effects of the adipokine hormone, leptin, are associated primarily with its action on receptors (ObRb) in the hypothalamus. Recently, however, ObRb mRNA has been reported in vagal afferent neurons, some of which also express CCK-1 receptor, suggesting that leptin, alone or in cooperation with CCK, might activate vagal afferent neurons, and influence food intake via a vagal route. To evaluate these possibilities we have been examining the cellular and behavioral effects of leptin and CCK on vagal afferent neurons. In cultured vagal afferent neurons leptin and CCK evoked short latency, transient depolarizations, often leading to action potentials, and increases in cytosolic calcium. There was a much higher prevalence of CCK and leptin sensitivity amongst cultured vagal afferent neurons that innervate stomach or duodenum than there was in the overall vagal afferent population. Furthermore, almost all leptin-responsive gastric and duodenal vagal afferents also were sensitive to CCK. Leptin, infused into the upper GI tract arterial supply, reduced meal size, and enhanced satiation evoked by CCK. These results indicate that vagal afferent neurons are activated by leptin, and that this activation is likely to participate in meal termination, perhaps by enhancing vagal sensitivity to CCK. Our findings are consistent with the view that leptin and CCK exert their influence on food intake by accessing multiple neural systems (viscerosensory, motivational, affective and motor) at multiple points along the neuroaxis.

The non-competitive NMDA antagonist MK-801 increases food intake in rats

A role for excitatory amino acids in the control of feeding behavior has not been extensively investigated. Nevertheless, there is direct and circumstantial evidence to indicate that some circuits involved with feeding behavior include glutamatergic elements. To test the hypothesis that endogenous glutamate participates in the control of food intake, we performed experiments to determine whether MK-801, a non-competitive N-methyl-D-aspartate (NMDA) ion channel antagonist, is capable of altering intake of liquid and solid foods in hungry or satiated rats. Following a 16 h fast, intake of 15% sucrose was significantly enhanced by systemic treatment with MK-801. Water intake was not altered by the NMDA antagonist. Rats did not ingest more rat chow after MK-801, unless they had been fasted. When a more palatable food (cookies) was offered, MK-801 did increase intake. Thus MK-801 enhanced food intake only when feeding was initiated by food-deprivation or increased palatability. In conclusion, our results support the hypothesis that endogenous glutamate plays a role in the control of food intake. Blockade of NMDA receptor function by MK-801 may diminish or delay satiety signals, rather than initiate feeding behavior per se.

Absence of glucoprivic feeding after stress suggests impairment of noradrenergic neuron function

Feeding in response to 2-deoxy-D-glucose (2DG), a quantifiable behavior which appears to depend on noradrenergic (NE) neuron function, was used in these experiments to evaluate the functional capabilities of NE neurons after stress exposure. Depletion of hypothalamic NE after footshock or hypothermic stress was directly correlated with impairment of glucoprivic feeding. When NE depletion was prevented by prior exposure to chronic stress, no impairment of feeding was observed. After hypothermic stress, repletion of NE proceeded more rapidly in the telencephalon than in the hypothalamus and reappearance of a normal feeding response precisely paralleled the time course of repletion in the hypothalamus. Drinking in response to cell dehydration, a behavior not directly dependent on brain catecholamines, was not impaired after either footshock or hypothermic stress, despite similar NE depletions. Presence of a normal drinking response assured that deficits observed in the 2DG test were not due to nonspecific behavioral suppression resulting from stress. These data suggest that NE neuron function may be impaired or temporarily abolished after severe stress exposure. In addition, these results demonstrate that behavioral pathology need not be the result of massive neurotransmitter depletion but may result from relatively subtle alterations of specific neurotransmitter pools.

Area postrema lesions increase drinking to angiotensin and extracellular dehydration.

The area postrema (AP) is a circumventricular organ of the caudal medulla oblongata. This structure lacks a blood brain barrier and contains high concentrations of angiotensin II (AII) receptors. Because AII is a participant in the arousal of thirst, we have examined the effect of AP lesions upon drinking in response to exogenous AII and in response to various thirst challenges. We have found that rats with AP lesions (APL) drink more water than control rats in response to isoproterenol and polyethylene glycol. Rats with AP lesions also drank two times as much water as controls in response to subcutaneous injection of exogenous AII. Ad lib water intakes of APL and control rats were not different. Furthermore, drinking in response to 21 hr water deprivation or cell dehydration did not differ for APL and control rats. Our results suggest that AP lesions selectively enhance extracellular thirst, especially the component of that thirst mediated by AII.