Joost Overduin

Gastrointestinal regulation of food intake

Despite substantial fluctuations in daily food intake, animals maintain a remarkably stable body weight, because overall caloric ingestion and expenditure are exquisitely matched over long periods of time, through the process of energy homeostasis. The brain receives hormonal, neural, and metabolic signals pertaining to body-energy status and, in response to these inputs, coordinates adaptive alterations of energy intake and expenditure. To regulate food consumption, the brain must modulate appetite, and the core of appetite regulation lies in the gut-brain axis. This Review summarizes current knowledge regarding the neuroendocrine regulation of food intake by the gastrointestinal system, focusing on gastric distention, intestinal and pancreatic satiation peptides, and the orexigenic gastric hormone ghrelin. We highlight mechanisms governing nutrient sensing and peptide secretion by enteroendocrine cells, including novel taste-like pathways. The increasingly nuanced understanding of the mechanisms mediating gut-peptide regulation and action provides promising targets for new strategies to combat obesity and diabetes.

Acyl and Total Ghrelin Are Suppressed Strongly by Ingested Proteins, Weakly by Lipids, and Biphasically by Carbohydrates

CONTEXT Ghrelin is an orexigenic hormone that can increase body weight. Its circulating levels increase before meals and are suppressed after food ingestion. Understanding the effects of specific types of ingested macronutrients on ghrelin regulation could facilitate the design of weight-reducing diets. OBJECTIVE We sought to understand how ingestion of carbohydrates, proteins, or lipids affect acyl (bioactive) and total ghrelin levels among human subjects, hypothesizing that lipids might suppress ghrelin levels less effectively than do either carbohydrates or proteins. DESIGN This was a randomized, within-subjects cross-over study. SETTING The study was conducted at a University Clinical Research Center. PARTICIPANTS There were 16 healthy human subjects included in the study. INTERVENTIONS Isocaloric, isovolemic beverages composed primarily of carbohydrates, proteins, or lipids were provided. MAIN OUTCOME MEASURES The magnitude of postprandial suppression of total and acyl ghrelin levels (measured with a novel acyl-selective, two-site ELISA) was determined. RESULTS All beverages suppressed plasma acyl and total ghrelin levels. A significant effect of macronutrient class on decremental area under the curve for both acyl and total ghrelin was observed; the rank order for magnitude of suppression was protein more than carbohydrate more than lipid. Total ghrelin nadir levels were significantly lower after both carbohydrate and protein, compared with lipid beverages. In the first 3 postprandial hours, the rank order for acyl and total ghrelin suppression was carbohydrate more than protein more than lipid. In the subsequent 3 h, there was a marked rebound above preprandial values of acyl and total ghrelin after carbohydrate ingestion alone. CONCLUSIONS These findings suggest possible mechanisms contributing to the effects of high-protein/low-carbohydrate diets to promote weight loss, and high-fat diets to promote weight gain.

Normal feeding and body weight in Fischer 344 rats lacking the cholecystokinin-1 receptor gene

A large body of evidence has demonstrated that one mechanism by which cholecystokinin (CCK) inhibits food intake through activation of CCK1 receptors (CCK1R) on vagal afferent neurons that innervate the gastrointestinal tract and project to the hindbrain. OLETF rats, which carry a spontaneous null mutation of the CCK1R, are hyperphagic, obese, and predisposed to type 2 diabetes. Recently, by introgressing the OLETF-derived, CCK1R-null gene onto a Fischer 344 genetic background, we have been able to generate a CCK1R-deficient, congenic rat strain, F344.Cck1r(-/-), that in contrast to OLETF rats, possesses a lean and normoglycemic phenotype. In the present study, the behavioral and neurobiological phenotype of this rat strain was characterized more fully. As expected, intraperitoneal injections of CCK-8 inhibited intake of chow and Ensure Plus and induced Fos responses in the area postrema and the gelatinosus, commissural and medial subdivisions of the nucleus tractus solitarius of wild-type F344.Cck1r(+/+) rats, whereas CCK-8 was without effect on food intake or Fos induction in the F344.Cck1r(-/-) rats. F344.Cck1r(-/-) and F344.Cck1r(+/+) rats did not differ in body weight and showed comparable weight gain when maintained on Ensure Plus for 2 weeks. Also, no difference was found in 24-h food intake, and dark-phase meal frequency or meal size between F344.Cck1r(+/+) and F344.Cck1r(-/-) rats. As expected, blockade of endogenous CCK action at CCK1R increased food intake and blocked the effects of peripheral CCK-8 in wild-type F344.Cck1r(+/+) rats. These results confirm that in rats with a F344 background, CCK-1R mediates CCK-8-induced inhibition of food intake and Fos activation in the hindbrain and demonstrate that selective genetic ablation of CCK1R is not associated with altered meal patterns, hyperphagia, or excessive weight gain on a palatable diet.

Roles for ghrelin in the regulation of appetite and body weight

Purpose of reviewGhrelin, the only known circulating appetite stimulant, has garnered widespread scientific interest and is currently featured in more than 2.3 new publications per day. Antagonists and agonists of its receptor are vigorously being developed by pharmaceutical companies to treat obesity and wasting conditions respectively. Here, the authors summarize the current state of knowledge regarding ghrelins roles in energy homeostasis. Recent findingsGhrelin is an acylated peptide produced primarily by the stomach and proximal small intestine. Circulating levels sharply increase before, and decrease after, meals. These and other findings implicate ghrelin in pre-meal hunger and meal initiation. Moreover, ghrelin satisfies established criteria for an adiposity-associated hormone involved in long-term body weight regulation. Blood levels correlate with energy stores and display compensatory changes in response to alterations of those stores. Ghrelin influences neuronal activity in brain areas critical to energy homeostasis. Excessive ghrelin signaling durably increases food intake and decreases energy expenditure, thereby promoting weight gain. Conversely, acute ghrelin blockade in adult animals reduces food intake and body weight, although the effects of lifelong genetic deletions are very subtle. Overproduction of ghrelin is etiologically implicated in Prader-Willi syndrome, whereas defective secretion may contribute to weight loss after gastric bypass surgery. SummaryGhrelin appears to participate in mealtime hunger and meal initiation, as well as in long-term energy balance. Whether these roles are sufficiently important that ghrelin blockade will prove to be an effective antiobesity modality is a pivotal question that should soon be answered as ghrelin receptor antagonists are developed. Ghrelin agonists hold promise in the treatment of wasting conditions, for which few medications currently exist.

Circulating Ghrelin Levels in Pathophysiological Conditions

Circulating levels of ghrelin, are regulated by short-term factors pertaining to food ingestion and longer-term factors pertaining to body weight. The short-term, or prandial, regulation is manifest as marked increases in ghrelin levels before each meal and decreases after food is consumed. This temporal pattern, implicates ghrelin as a contributor to pre-meal hunger and the initiation of individual meals. Long-term, body weight-related regulation of ghrelin results in a negative relationship between ghrelin levels and numerous measures of body size. This association and several other findings suggest that ghrelin may participate not only in the short-term control of meal patterns but also in overall body-weight regulation. Ghrelin fulfills all of the established criteria to be an “adiposity signal” that senses the status of body-fat stores and communicates this information to the brain, which activates compensatory changes in appetite and energy expenditure designed to maintain homeostasis. Ghrelin levels vary in response to alterations in energy balance, increasing with weight loss and thus potentially contributing to the compensatory hyperphagia triggered by negative energy balance. The opposite is true for weight gain. Most of the alterations of circulating ghrelin levels in pathophysiological conditions can be viewed as adaptive responses to the body-weight perturbations in these disorders. The only known exception is Prader-Willi syndrome, a condition in which hyperghrelinemia may play a primary, causal role driving hyperphagia and obesity. These patients represent logical subjects in whom first to test the efficacy of ghrelin-blocking agents to treat obesity. Low fat diets promote modest weight loss without triggering the normal compensatory increase in ghrelin levels, and gastric bypass surgery can suppress (or at least constrain) ghrelin levels in most cases. The impact of these interventions on circulating ghrelin may contribute to their weightreducing effects.

Hyperosmolarity in the small intestine contributes to postprandial ghrelin suppression

Plasma levels of the orexigenic hormone ghrelin are suppressed by meals with an efficacy dependent on their macronutrient composition. We hypothesized that heterogeneity in osmolarity among macronutrient classes contributes to these differences. In three studies, the impact of small intestinal hyperosmolarity was examined in Sprague-Dawley rats. In study 1, isotonic, 2.5×, and 5× hypertonic solutions of several agents with diverse absorption and metabolism properties were infused duodenally at a physiological rate (3 ml/10 min). Jugular vein blood was sampled before and at 30, 60, 90, 120, 180, 240, and 300 min after infusion. Plasma ghrelin was suppressed dose dependently and most strongly by glucose. Hyperosmolar infusions of lactulose, which transits the small intestine unabsorbed, and 3-O-methylglucose (3-O-MG), which is absorbed like glucose but remains unmetabolized, also suppressed ghrelin. Glucose, but not lactulose or 3-O-MG, infusions increased plasma insulin. In study 2, intestinal infusions of hyperosmolar NaCl suppressed ghrelin, a response that was not attenuated by coinfusion with the neural blocker lidocaine. In study 3, we reconfirmed that the low-osmolar lipid emulsion Intralipid suppresses ghrelin more weakly than isocaloric (but hypertonic) glucose. Importantly, raising Intralipids osmolarity to that of the glucose solution by nonabsorbable lactulose supplementation enhanced ghrelin suppression to that seen after glucose. Hyperosmolar ghrelin occurred particularly during the initial 3 postinfusion hours. We conclude that small intestinal hyperosmolarity 1) is sufficient to suppress ghrelin, 2) may combine with other postprandial mechanisms to suppress ghrelin, 3) might contribute to altered ghrelin regulation after gastric bypass surgery, and 4) may inform dietary modifications for metabolic health.