Arline D. Salbe

Neuroimaging and obesity: mapping the brain responses to hunger and satiation in humans using positron emission tomography.

Abstract: The hypothalamus has a major role in the control of food intake. However, neurotracing studies have shown that the hypothalamus receives input from several other regions of the brain that are likely to modulate its activity. Of particular interest to the understanding of human eating behavior is the possible involvement of the cortex. Using positron emission tomography (PET), we generated functional brain maps of the neuroanatomical correlates of hunger (after a 36‐h fast) and satiation (after oral administration of a liquid formula meal) in lean and obese subjects. Results in lean individuals indicate that the neuroanatomical correlates of hunger form a complex network of brain regions including the hypothalamus, thalamus, and several limbic/paralimbic areas such as the insula, hippocampal/parahippocampal formation, and the orbitofrontal cortex. Satiation was associated with preferentially increased neuronal activity in the prefrontal cortex. Our studies also indicate that the brain responses to hunger/satiation in the hypothalamus, limbic/paralimbic areas (commonly associated with the regulation of emotion), and prefrontal cortex (thought to be involved in the inhibition of inappropriate response tendencies) might be different in obese and lean individuals. In conclusion, neuroimaging of the human brain is proving to be an important tool for understanding the complexity of brain involvement in the regulation of eating behavior. PET studies might help to unravel the neuropathophysiology underlying human obesity.

Sensory experience of food and obesity: a positron emission tomography study of the brain regions affected by tasting a liquid meal after a prolonged fast.

The sensory experience of food is a primary reinforcer of eating and overeating plays a major role in the development of human obesity. However, whether the sensory experience of a forthcoming meal and the associated physiological phenomena (cephalic phase response, expectation of reward), which prepare the organism for the ingestion of food play a role in the regulation of energy intake and contribute to the development of obesity remains largely unresolved. We used positron emission tomography (PET) and 15O-water to measure changes in regional cerebral blood flow (rCBF) and to assess the brains response to the oral administration of 2 ml of a liquid meal (Ensure Plus, 1.5 kcal/ml) after a 36-h fast and shortly before consuming the same meal. Twenty-one obese (BMI > 35 kg/m2, 10M/11F, age 28 +/- 6 years, body fat 40 +/- 6%) and 20 lean individuals (BMI < 25 kg/m2, 10M/10F, age 33 +/- 9 years, body fat 21 +/- 7%) were studied. Compared to lean individuals, obese individuals had higher fasting plasma glucose (83.3 +/- 6.2 vs. 75.5 +/- 9.6 mg/dl; P = 0.0003) and insulin concentrations (6.1 +/- 3.5 vs. 2.5 +/- 1.7 microU/ml; P < 0.0001) and were characterized by a higher score of dietary disinhibition (i.e., the susceptibility of eating behavior to emotional factors and sensory cues, 5.7 +/- 3.6 vs. 3.5 +/- 2.7; P = 0.01) assessed by the Three Factor Eating Questionnaire. In response to the sensory experience of food, differences in rCBF were observed in several regions of the brain, including greater increases in the middle-dorsal insula and midbrain, and greater decreases in the posterior cingulate, temporal, and orbitofrontal cortices in obese compared to lean individuals (P < 0.05, after small volume correction). In a multiple regression model, percentage of body fat (P = 0.04), glycemia (P = 0.01), and disinhibition (P = 0.07) were independent correlates of the neural response to the sensory experience of the meal in the middle-dorsal insular cortex (R2 = 0.45). We conclude that obesity is associated with an abnormal brain response to the sensory aspects of a liquid meal after a prolonged fast especially in areas of the primary gustatory cortex. This is only partially explained by the elevated glycemia and high level of disinhibition which characterize individuals with increased adiposity. These results provide a new perspective on the understanding of the neuroanatomical correlates of abnormal eating behavior and their relationship with obesity in humans.

Higher sedentary energy expenditure in patients with Huntington's disease

Weight loss is common among patients with Huntingtons disease (HD), although the mechanisms contributing to this phenomenon are not known. We measured 24‐hour sedentary energy expenditure (24‐hour EE) and sleeping metabolic rate (SMR) in a human respiratory chamber in 17 patients with mild to moderate HD and 17 control subjects matched for age, sex, and body mass index. Total energy expenditure was measured during 7 days in free‐living conditions, using the doubly labeled water technique. Body weight, fat mass, and fat‐free mass (measured by dual‐energy x‐ray absorptiometry) were similar in patients with HD and control subjects. Twenty‐four‐hour EE was 14% higher in HD patients than controls in absolute terms (2,038 ± 98 vs 1,784 ± 68 kcal/24 hours) and after adjustment for age, sex, fat mass, and fat‐free mass (1,998 ± 45 vs 1,824 ± 45 kcal/24 hours). In contrast, SMR and total energy expenditure were similar in patients and controls both in absolute terms (1,314 ± 38 vs 1,316 ± 42 and 2,402 ± 102 vs 2,373 ± 98 kcal/24 hours, respectively) and after adjustment. Spontaneous physical activity measured by radar in the chamber and the ratio of 24‐hour EE to SMR were significantly higher in HD patients than controls (11.4 ± 1.4 vs 6.1 ± 0.6% and 1.54 ± 0.05 vs 1.36 ± 0.03, respectively). In the group as a whole, 24‐hour EE/SMR correlated with spontaneous physical activity. Among HD patients, both 24‐hour EE/SMR and spontaneous physical activity correlated with the severity of chorea, but SMR and total energy expenditure did not. There were no differences in reported energy intake during 7 days in patients with HD compared with controls. The results of this study indicate that sedentary energy expenditure is higher in patients with HD than in controls in proportion to the severity of the movement disorder. Total free‐living energy expenditure is not higher, however, because patients with HD appear to engage in less voluntary physical activity. Ann Neurol 2000; 47:64–70

Postprandial glucagon-like peptide-1 (GLP-1) response is positively associated with changes in neuronal activity of brain areas implicated in satiety and food intake regulation in humans.

Postprandial glucagon-like peptide-1 (GLP-1) secretion can act as a meal termination signal in animals and humans. We tested the hypothesis that the postprandial changes in plasma GLP-1 concentrations are associated with changes in the human brain activity in response to satiety by performing a post-hoc analysis of a cross-sectional study of neuroanatomical correlates of hunger and satiation using (15)O-water positron-emission tomography (PET). Forty-two subjects (22M/20F, age 31+/-8 years) spanning a wide range of adiposity (body fat: 7-44%) were included in this analysis. Outcome measures included changes in PET-measured regional cerebral blood flow (rCBF) and plasma concentrations of GLP-1, glucose, insulin, and free-fatty acids (FFA), elicited by the administration of a satiating amount of a liquid formula meal. The peak postprandial increases in plasma GLP-1 concentrations were correlated with increases in rCBF in the left dorsolateral prefrontal cortex (including the left middle and inferior frontal gyri), previously implicated in PET studies of human satiation, and the hypothalamus, previously implicated in the regulation of food intake in animal and human studies, both before and after adjustment for sex, age, body fat, and changes in plasma glucose, insulin, and serum FFA concentrations. The postprandial GLP-1 response is associated with activation of areas of the human brain previously implicated in satiation and food intake regulation.

Physiological Evidence for the Involvement of Peptide YY in the Regulation of Energy Homeostasis in Humans

Objective: To explore the potential role of the endogenous peptide YY (PYY) in the long‐term regulation of body weight and energy homeostasis.

Tasting a liquid meal after a prolonged fast is associated with preferential activation of the left hemisphere

We used positron emission tomographic scanning of the brain and measures of regional cerebral blood flow to investigate the response of 44 right-handed people to the oral administration of 2 ml of a liquid formula meal after a 36 h fast (and shortly before the administration of a satiating amount of the same meal). Several areas of the left hemisphere were significantly more activated than the contralateral, including the frontal operculum, ventral insula, and piriform cortex. In contrast with reports of right-hemisphere dominance in chemosensory perception in non-hungry individuals, our study reveals a preferential activation of the left hemisphere when people who are very hungry are briefly exposed to the chemical and physical properties of a liquid meal. This raises the possibility that the physiological context in which perception takes place (i.e. extreme vs moderate vs no hunger) may importantly affect the brain representation of chemosensory stimuli.

Higher 24-h respiratory quotient and higher spontaneous physical activity in nighttime eaters.

We have previously shown that a higher 24‐h respiratory quotient (24‐h RQ) predicts greater ad‐libitum food intake and that nighttime eaters (NE) ingested more calories during an in‐patient food intake study and gained more weight over time. We investigated whether 24‐h RQ was higher in individuals who exhibited nighttime eating behavior. Healthy nondiabetic Pima Indians (PI; n = 97, 54 male/43 female) and whites (W; n = 32, 22 male/10 female) were admitted to our Clinical Research Unit. After 3 days of a weight maintaining diet, 24‐h energy expenditure (24‐h EE), 24‐h RQ, rates of carbohydrate (CHOX) and lipid oxidation (LIPOX), and spontaneous physical activity (SPA) were measured in a metabolic chamber whereas volunteers were in energy balance and unable to consume excess calories. Individuals subsequently ate ad libitum from a computerized vending machine for 3 days with amount and timing of food intake recorded. Fifty‐five individuals (36%; 39 PI, 16 W) were NE, who ate between 11 pm and 5 am on at least one of the 3 days on the vending machines. There were no differences in BMI or percentage body fat between NE and non‐NE. After adjusting for age, sex, race, fat‐free mass, fat mass, and energy balance, NE had a higher 24‐h RQ (P = 0.01), higher CHOX (P = 0.009), and lower LIPOX (P = 0.03) and higher 24‐h SPA (P = 0.04) compared to non‐NE. There were no differences in adjusted 24‐h EE or sleep RQ between the groups. Individuals with nighttime eating behavior have higher 24‐h RQ, higher CHOX and lower LIPOX, a phenotype associated with increased food intake and weight gain.

Reproducibility of ad libitum energy intake with the use of a computerized vending machine system

BACKGROUND Accurate assessment of energy intake is difficult but critical for the evaluation of eating behavior and intervention effects. Consequently, methods to assess ad libitum energy intake under controlled conditions have been developed. OBJECTIVE Our objective was to evaluate the reproducibility of ad libitum energy intake with the use of a computerized vending machine system. DESIGN Twelve individuals (mean + or - SD: 36 + or - 8 y old; 41 + or - 8% body fat) consumed a weight-maintaining diet for 3 d; subsequently, they self-selected all food with the use of a computerized vending machine system for an additional 3 d. Mean daily energy intake was calculated from the actual weight of foods consumed and expressed as a percentage of weight-maintenance energy needs (%WMEN). Subjects repeated the study multiple times during 2 y. The within-person reproducibility of energy intake was determined through the calculation of the intraclass correlation coefficients (ICCs) between visits. RESULTS Daily energy intake for all subjects was 5020 + or - 1753 kcal during visit 1 and 4855 + or - 1615 kcal during visit 2. There were no significant associations between energy intake and body weight, body mass index, or percentage body fat while subjects used the vending machines, which indicates that intake was not driven by body size or need. Despite overconsumption (%WMEN = 181 + or - 57%), the reproducibility of intake between visits, whether expressed as daily energy intake (ICC = 0.90), %WMEN (ICC = 0.86), weight of food consumed (ICC = 0.87), or fat intake (g/d; ICC = 0.87), was highly significant (P < 0.0001). CONCLUSION Although ad libitum energy intake exceeded %WMEN, the within-person reliability of this intake across multiple visits was high, which makes this a reproducible method for the measurement of ad libitum intake in subjects who reside in a research unit. This trial was registered at clinicaltrials.gov as NCT00342732.

Glucose response to an oral glucose tolerance test predicts weight change in non-diabetic subjects.

Objective: Glucose exerts a dual action in the regulation of energy balance, consisting of inhibition of energy intake and stimulation of energy expenditure. Whether blood glucose affects long‐term regulation of body weight in humans remains to be established. We sought to test the hypothesis that the post‐challenge glucose response is a predictor of weight change.

A human model of dietary saturated fatty acid induced insulin resistance

BACKGROUND Increased consumption of high-fat diets is associated with the development of insulin resistance and type 2 diabetes. Current models to study the mechanisms of high-fat diet-induced IR in humans are limited by their long duration or low efficacy. In the present study we developed and characterized an acute dietary model of saturated fatty acid-enriched diet induced insulin resistance. METHODS High caloric diets enriched with saturated fatty acids (SFA) or carbohydrates (CARB) were evaluated in subjects with normal and impaired glucose tolerance (NGT or IGT). Both diets were compared to a standard eucaloric American Heart Association (AHA) control diet in a series of crossover studies. Whole body insulin resistance was estimated as steady state plasma glucose (SSPG) concentrations during the last 30min of a 3-h insulin suppression test. RESULTS SSPG was increased after a 24-h SFA diet (by 83±74% vs. control, n=38) in the entire cohort, which was comprised of participants with NGT (92±82%, n=22) or IGT (65±55%, n=16) (all p<0.001). SSPG was also increased after a single SFA breakfast (55±32%, p=0.008, n=7). The increase in SSPG was less pronounced after an overnight fast following a daylong SFA diet (24±31%, p=0.04, n=10), and further attenuated 24h after returning to the control diet (19±35%, p=0.09, n=11). SSPG was not increased after a 24-h CARB diet (26±50%, p=0.11, n=12). CONCLUSIONS A short-term SFA-enriched diet induced whole body insulin resistance in both NGT and IGT subjects. Insulin resistance persisted overnight after the last SFA meal and was attenuated by one day of a healthy diet. This model offers opportunities for identifying early mechanisms and potential treatments of dietary saturated fat induced insulin resistance.