Sami A. Hashim

Peripheral and central signals in the control of eating in normal, obese and binge-eating human subjects

The worldwide increase in the incidence of obesity is a consequence of a positive energy balance, with energy intake exceeding expenditure. The signalling systems that underlie appetite control are complex, and the present review highlights our current understanding of key components of these systems. The pattern of eating in obesity ranges from over-eating associated with binge-eating disorder to the absence of binge-eating. The present review also examines evidence of defects in signalling that differentiate these sub-types. The signalling network underlying hunger, satiety and metabolic status includes the hormonal signals leptin and insulin from energy stores, and cholecystokinin, glucagon-like peptide-1, ghrelin and peptide YY3-36 from the gastrointestinal tract, as well as neuronal influences via the vagus nerve from the digestive tract. This information is routed to specific nuclei of the hypothalamus and brain stem, such as the arcuate nucleus and the solitary tract nucleus respectively, which in turn activate distinct neuronal networks. Of the numerous neuropeptides in the brain, neuropeptide Y, agouti gene-related peptide and orexin stimulate appetite, while melanocortins and alpha-melanocortin-stimulating hormone are involved in satiety. Of the many gastrointestinal peptides, ghrelin is the only appetite-stimulating hormone, whereas cholecystokinin, glucagon-like peptide-1 and peptide YY3-36 promote satiety. Adipose tissue provides signals about energy storage levels to the brain through leptin, adiponectin and resistin. Binge-eating has been related to a dysfunction in the ghrelin signalling system. Moreover, changes in gastric capacity are observed, and as gastric capacity is increased, so satiety signals arising from gastric and post-gastric cues are reduced. Understanding the host of neuropeptides and peptide hormones through which hunger and satiety operate should lead to novel therapeutic approaches for obesity; potential therapeutic strategies are highlighted.

Gastric capacity in normal, obese, and bulimic women

One function of the stomach is as a reservoir for food; hence, the stomachs capacity may limit the amount of food ingested. A stomach with a large capacity has been associated with bigger test meals. We compared the stomach capacity of three groups of women: normal (n=10), obese (n=11), and bulimic (n=10). Following an overnight fast, gastric capacity was estimated by filling a gastric balloon with water at 100 ml/min, with pauses for measuring intragastric pressure. One estimate was based on the maximum volume the subject could tolerate as indicated by a maximal rating of abdominal discomfort. Another estimate was based on the volume required to produce a given rise of intragastric pressure, 5 cm H(2)O. A third related measure was based on a maximal rating of fullness. Based on these estimates, the gastric capacity of the bulimics was the largest, with the obese subjects intermediate. We then separated the obese subjects according to whether they reported binge eating (n=6) or not (n=5). The gastric capacity of the binge-eating subset was similar to the bulimics, and the nonbinge-eating subset was similar to the normals. Thus, gastric capacity appears more related to binge eating behavior than to body weight.

A new method for estimation of body composition in the live rat.

Abstract Measurement of total body electrical conductivity (TOBEC) has been used to estimate lean and fat content of meat based on the principle that electrical conductivity of lean tissue is far greater than that of fat. This approach was used to estimate body composition of live rats. An instrument designed for commercial analysis of ground meat (DjMe 100) was used to measure TOBEC in 30 male Sprague-Dawley rats (197-433 g). Individual TOBEC values were obtained in 20 seconds and repeated twice for each rat. The animals were then killed with ether, hair was shaved, lungs collapsed and body density measured hydrostatically. Carcasses were homogenized and analyzed for fat, nitrogen, and water. A high correlation was found between TOBEC and lean body mass by densitometry (r = .97) and between TOBEC and fat-free mass derived from direct carcass analysis (r = .97). Rats weighing up to 450 g could be accommodated in this particular instrument. Measurement of TOBEC should prove useful in estimating body composition and monitoring its changes in live rats and other small laboratory animals.

Medium chain triglyceride in early life: effects on growth of adipose tissue

Effects of feeding early in life a diet high in either long chain (LCT) or medium chain triglyceride (MCT) were studied on the development of adipose tissue in post-weanling rats. The diets were similar in calorie distribution and identical in nutrients except for type of fat. The caloric distribution of the two diets by percent was LCT (corn oil)/protein/carbohydrate, 70/18/12 and MCT/corn oil/protein/carbohydrate, 66/4/18/12. Male littermates with less than 5% weight difference were pair-fed the two diets randomly at age 18–20 days. One-fourth of the rats were killed at 10, 16, 22 and 28 weeks of age and analyzed for adipose depots and adipose tissue cellularity. Results showed that the LCT-fed rats were significantly heavier, with larger epididymal, retroperitoneal, omental and subcutaneous fat pads than the respective pair-fed MCT rats. Also, LCT-fed rats had larger size and number of adipocytes than MCT-fed littermates. It is concluded that the type of fat in the diet, namely LCT or MCT, when fed early in life can influence the development of adipose tissue. MCT appears less lipogenic than LCT. The mechanism for the diminished adiposity of MCT-fed rats is related to extensive oxidation of MCT and its enhancement of thermogenesis leading to lessened energy efficiency.

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

Ketone bodies (KBs), acetoacetate and β-hydroxybutyrate (βHB), were considered harmful metabolic by-products when discovered in the mid-19th century in the urine of patients with diabetic ketoacidosis. It took physicians many years to realize that KBs are normal metabolites synthesized by the liver and exported into the systemic circulation to serve as an energy source for most extrahepatic tissues. Studies have shown that the brain (which normally uses glucose for energy) can readily utilize KBs as an alternative fuel. Even when there is diminished glucose utilization in cognition-critical brain areas, as may occur early in Alzheimer’s disease (AD), there is preliminary evidence that these same areas remain capable of metabolizing KBs. Because the ketogenic diet (KD) is difficult to prepare and follow, and effectiveness of KB treatment in certain patients may be enhanced by raising plasma KB levels to ≥2 mM, KB esters, such as 1,3-butanediol monoester of βHB and glyceryl-tris-3-hydroxybutyrate, have been devised. When administered orally in controlled dosages, these esters can produce plasma KB levels comparable to those achieved by the most rigorous KD, thus providing a safe, convenient, and versatile new approach to the study and potential treatment of a variety of diseases, including epilepsy, AD, and Parkinson’s disease.

Experimentally induced hyperketonemia and insulin secretion in the dog

Abstract Effects of varying magnitudes of experimentally induced hyperketonemia on immunoreactive insulin (IRI) secretion were studied in dogs. During one-hour infusion of 7.0 mMoles/Kg./hr. of DL sodium beta hydroxybutyrate, mean ± SE serum ketones rose to 37.4 ± 3.2 mg. per 100 ml. at one hour, while glucose fell to 65.6 ± 2.7 per cent of control, both returning toward baseline after completion of infusion. A 2.5-fold rise in IRI (12.4 ± 1.2 to 30.7 ± 4.7 μU/ml.) occurred at 5 minutes, followed by gradual decline to baseline after cessation of infusion. Infusion of 3.5 mMoles/Kg./hr. was associated with a smaller magnitude but a similar pattern of change. Infusion of 1.0 mMole/Kg./hr. caused no significant change in glucose or IRI, while ketones reached 3.7 ± 0.9 mg. per 100 ml. In rapid (1 minute) infusion of varying amounts (16 to 79 mMoles) of ketone, prompt responses in IRI were elicited in proportion to quantity of ketone administered. In experiments in which portal venous blood was obtained, portal: arterial IRI gradients of 2–3:1 were observed. The results indicate a relationship between the degree of hyperketonemia, insulin response, and hypoglycemia, and suggest that hyperketonemia of degrees encountered during lipolytic states may provide a feedback effect on adipose tissue mediated by insulin.

Altered Sedimentation Behavior and Ultrastructure of Platelets in Hyperlipidemia

The influence of hyperlipidemia on platelet sedimentation behavior and ultrastructure was studied in samples of plasma obtained from 22 normal subjects, 7 patients with Type II and 12 patients with Type IV hyperlipoproteinemia, all fasting; also from 11 normal subjects prior to and at intervals up to 6 hours following ingestion of a meal containing 65 g of fat. Platelet counts were made on mixed platelet rich plasma after centrifugation of whole blood at 1,000 rpm, on top plasma layers after high speed centrifugation (10,000 rpm), and on the sediments resuspended in imidazole buffer. The mean ± SE number of platelets per mm3 in top layer among normal, Type II and Type IV plasmas were 4,090 ± 405; 9,000 ± 70, and 21,500 ± 1,950, respectively. The rise and subsequent fall in plasma triglycerides in response to fat ingestion in normal subjects paralleled those of platelets in the top layers. No such correlation was found with plasma cholesterol. The presence of platelets in the top layers of plasma was demonstrated further by electron microscopy. The buoyant platelets revealed the presence of osmophilic (lipid) particles within their open canalicular system, and pseudopod formation. The sedimented platelets from normal subjects had a smooth contour, whereas those from patients with hyperlipidemia displayed a striking formation of pseudopods. The data suggest that the sedimentation behavior of platelets and their normal structure are altered significantly as they interact with abnormal concentrations of plasma lipoproteins.

The Rationale, Feasibility, and Optimal Training of the Non-Physician Medical Nutrition Scientist

Dietary components have potential to arrest or modify chronic disease processes including obesity, cancer, and comorbidities. However, clinical research to translate mechanistic nutrition data into clinical interventions is needed. We have developed a one-year transitional postdoctoral curriculum to prepare nutrition scientists in the language and practice of medicine and in clinical research methodology before undertaking independent research. Candidates with an earned doctorate in nutrition science receive intensive, didactic training at the interface of nutrition and medicine, participate in supervised medical observerships, and join ongoing clinical research. To date, we have trained four postdoctoral fellows. Formative evaluation revealed several learning barriers to this training, including deficits in prior medical science knowledge and diverse perceptions of the role of the translational nutrition scientist. Several innovative techniques to address these barriers are discussed. We propose the fact that this “train the trainer” approach has potential to create a new translational nutrition researcher competent to identify clinical problems, collaborate with clinicians and researchers, and incorporate nutrition science across disciplines from “bench to bedside.” We also expect the translational nutrition scientist to serve as an expert resource to the medical team in use of nutrition as adjuvant therapy for the prevention and management of chronic disease.