Janis S. Fisler

Experimental obesity: a homeostatic failure due to defective nutrient stimulation of the sympathetic nervous system.

The basic hypothesis of this review is that studies on models of experimental obesity can provide insight into the control systems regulating body nutrient stores in humans. In this homeostatic or feedback approach to analysis of the nutrient control system, we have examined the afferent feedback signals, the central controller, and the efferent control elements regulating the controlled system of nutrient intake, storage, and oxidation. The mechanisms involved in the beginning and ending of single meals must clearly be related to the long-term changes in fat stores, although this relationship is far from clear. Changes in total nutrient storage in adipose tissue can arise as a consequence of changes in the quantity of nutrients ingested in one form or another or a decrease in the utilization of the ingested nutrients. A change in energy intake can be effected by increased size of individual meals, increased number of meals in a 24-hour period, or a combination of these events. Similarly, a decrease in utilization of these nutrients can develop through changes in resting metabolic energy expenditure which are associated with one of more of the biological cycles such as protein metabolism, triglyceride for glycogen synthesis and breakdown, or maintenance of ionic gradients for Na+ + K+ across cell walls. In addition, differences in energy expenditure related to the thermogenesis of eating or to the level of physical activity may account for differences in nutrient utilization.

Cardiac effects of starvation and semistarvation diets: safety and mechanisms of action.

A major concern with the use of starvation or semistarvation diets for weight reduction in severely obese people has been the reports of sudden death due to ventricular arrhythmias. Obesity per se is associated with cardiovascular changes, including left ventricular hypertrophy and prolongation of the QT interval. With weight loss, the mass of the heart and left ventricle decrease, but some signs of left ventricular dysfunction remain. The effect of weight loss on the electrocardiogram abnormalities of obesity appears to depend upon diet duration and upon whether protein and mineral nutritional status is maintained. Copper, potassium, and magnesium deficiencies may play important roles in promoting an electrically unstable heart. Stress, by eliciting autonomic imbalance, may act upon an electrically unstable heart to provoke acute arrhythmias in a subset of the obese population with QT interval prolongation.

Peripheral 3-hydroxybutyrate and food intake in a model of dietary-fat induced obesity: Effect of vagotomy ☆

We have examined the effect of peripheral 3-hydroxybutyrate injections on food intake and the contribution of the vagus nerve in the resistance to dietary fat-induced obesity in a rodent model. S 5B/Pl rats, which are resistant to dietary-fat induced obesity, and Osborne-Mendel rats, which are sensitive, were adapted to reverse light cycle. Food intake was measured for 24 h following the injection of 3-hydroxybutyrate, lactate, or glycerol (all 5 mMol/kg0.75, SC) at the onset of dark. Three-hydroxybutyrate reduced food intake (p < 0.0001) in S 5B/Pl rats only. Lactate reduced food intake slightly (p < 0.009) in both strains and glycerol had no effect on food intake. In a second experiment, S 5B/Pl and Osborne-Mendel rats were adapted to a high-fat diet and were then subjected to either selective hepatic vagotomy or sham operation. Vagotomy had no effect on weight gain of Osborne-Mendel rats but allowed weight gain in S 5B/Pl rats (p < 0.0001). Even in vagotomized S 5B/Pl rats, however, blood 3-hydroxybutyrate levels were inversely associated (r = -0.50) with food intake. These data suggest that the hepatic vagus nerve may contribute to the resistance of S 5B/Pl rats to dietary-fat induced obesity, but the data do not rule out a strictly central role for the regulation of food intake by 3-hydroxybutyrate in this strain.

Brain 3-hydroxybutyrate, glutamate, and GABA in a rat model of dietary obesity

Whole brain concentrations of 3-hydroxybutyrate, glutamate and gamma-aminobutyric acid (GABA) have been measured in two strains of rats with differing susceptibility to obesity. S 5B/Pl rats are resistant to developing obesity when eating a high-fat diet, whereas Osborne-Mendel rats readily develop obesity when eating the same diet. We tested the hypotheses that brain 3-hydroxybutyrate, glutamate and GABA differ between S 5B/Pl rats and Osborne-Mendel rats, and that these substrates/neuroregulators are altered when eating a high-fat diet primarily in S 5B/Pl (resistant) rats. Blood and brain 3-hydroxybutyrate concentrations were higher in S 5B/Pl rats than in Osborne-Mendel rats (p less than 0.05) but diet effects were not significant. Brain glutamate concentration, like 3-hydroxybutyrate, was higher in S 5B/Pl rats than in Osborne-Mendel rats (p less than 0.01) and was not affected by adding fat to the diet. Brain GABA differed only slightly between strains but increased after adding fat to the diet (p less than 0.05) in both strains with a greater increase occurring in S 5B/Pl rats. The brains of S 5B/Pl rats are chronically exposed to higher levels of 3-hydroxybutyrate and glutamate than are those of Osborne-Mendel rats. Thus, 3-hydroxybutyrate is a potential signal in the regulation of body weight. Brain GABA increases with fat feeding, especially in S 5B/Pl rats, suggesting that the ability to adjust to an energy dense diet may be through suppression of food intake by elevated brain GABA.

d-Fenfluramine in a rat model of dietary fat-induced obesity

d-Fenfluramine is an appetite suppressant drug that acts by releasing serotonin from axon terminals and inhibiting its reuptake. S 5B/P1 rats, which are resistant to dietary-fat induced obesity, and Osborne-Mendel rats, which are sensitive, were adapted to ad lib feeding of either a low- or high-fat diet. d-Fenfluramine (10 mg/kg, IP) was injected daily for 12 days. Other than a slightly greater suppression of food intake in Osborne-Mendel rats, there was little difference in response to d-fenfluramine between S 5B/P1 and Osborne-Mendel rats eating the low-fat diet. However, in Osborne-Mendel rats d-fenfluramine completely abolished the excess food intake and weight gain associated with the high-fat diet. Purine nucleotide (GDP) binding on day 13 was higher in S 5B/P1 rats than in Osborne-Mendel rats and was increased by d-fenfluramine in animals of both strains eating the low-fat diet. The high-fat diet increased GDP binding only in S 5B/P1 rats and blocked the fenfluramine-induced increase in GDP binding in both strains. We speculate that d-fenfluramine blocks a feeding reward system stimulated by the high-fat diet.

RELATIONSHIP BETWEEN THE CHANGES IN SERUM THYROID HORMONE LEVELS AND PROTEIN STATUS DURING PROLONGED PROTEIN SUPPLEMENTED CALORIC DEPRIVATION

The relationship between the changes in serum thyroid hormone levels and nitrogen economy during caloric deprivation were investigated in ten obese men during a 40 d, 400 kcal protein‐supplemented weight‐reducing diet. This regimen induced increases in the serum levels of total T4, free T4 and total rT3, and decreases of total T3, while serum TSH remained unchanged. There were progressive decreases in total body weight and urinary losses of total nitrogen and 3‐methylhistidine, with the early negative nitrogen balance gradually returning towards basal values during the 40 days. Subjects with the largest weight loss had the most increase in the serum levels of total T4 and free T4 index and the greatest decrease in T3. The magnitude of the increase of the nitrogen balance from its nadir was correlated with the extent of the reduction of T3 and increase of T3 uptake ratio and free T4 levels. The decrease in the urinary excretion of 3‐methylhistidine correlated with the increase in free T4 and rT3 levels. Nadir serum transferrin values were directly related to peak rT3 values, and the lowest albumin concentrations occurred in subjects with the highest total T4 and free T4 index values. Further, the maximum changes in the serum thyroid hormone levels preceded those of the nutritional parameters. These relationships suggest that: (1) increases in serum rT3 and free T4 and reductions in T3 concentrations during protein supplemented weight reduction may facilitate conservation of visceral protein and reduce muscle protein turnover; and (2) the variation in the magnitude of these changes may account for the heterogeneity of nitrogen economy.

Effect of a high-fat diet on firing rate of sympathetic nerves innervating brown adipose tissue in anesthetized rats ☆

Three experiments have examined the effects of ad lib and forced intake of a high-fat diet on sympathetic firing rate to brown adipose tissue. Seven days after beginning of ad lib intake of either a low-fat or high-fat diet, sympathetic activity was not significantly different in either group nor was it significantly different from the values obtained in animals measured at the switch from the chow to a semisynthetic high- or low-fat diet. After 22 days on the semisynthetic diet, however, the sympathetic firing rate of animals eating the high-fat diet had decreased nearly 25% and was significantly lower than the animals maintained on the semisynthetic low-fat diet or animals studied at the transition from the chow to the low-fat diet. In a second experiment animals were tube-fed for 3, 6 or 9 weeks on a high- or low-fat diet. Sympathetic firing rate of the rats eating the low-fat diet was higher at all three times, but the difference decreased with longer feeding. To eliminate differences in food intake, animals were tube-fed a moderate- or high-fat liquid diet three times a day for six days. The 80 kcal/day intake produced a steady weight gain in both groups. Liver weight, retroperitoneal white adipose tissue weight, and interscapular brown adipose tissue weight were all significantly greater in the animals fed the high-fat diet. Sympathetic firing rate, however, was significantly lower in the animals fed the high-fat semisynthetic diet as compared to animals fed the moderate-fat diet. These data show the high-fat diets are associated with a reduction in sympathetic activity to brown adipose tissue.

Metabolic and hormonal factors as predictors of nitrogen retention in obese men consuming very low calorie diets

The ability to conserve body protein during very low calorie diets in ten obese men was observed to correlate with plasma free amino acid concentrations, urinary N tau-methylhistidine: creatinine ratios, resting oxygen consumption, and serum triiodothyronine levels. A diet consisting of only protein, 1.3 g/kg ideal body weight/24 h, was given for 40 days. Cumulative nitrogen deficit ranged from -64 g to -227 g. Nitrogen balance on days 36 to 40 ranged from + 1.37 g/24 h to -3.30 g/24h. Nitrogen balance during this period had a significant direct correlation with pre-diet concentrations of branched-chain amino acids (r = 0.69 to 0.89), methionine (r = 0.85), histidine (r = 0.66), alanine (r = 0.73), arginine (r = 0.70), ornithine (r = 0.66), total essential (r = 0.87, and nonessential (r = 0.68) amino acids, with initial serum levels of triiodothyronine (r = 0.66) and with the fall in triiodothyronine over the 40 days (r = 0.79). Initial resting oxygen consumption was directly correlated (r = 0.78) with final nitrogen balance and inversely with total nitrogen loss (r = -0.81). On day 0, triiodothyronine levels also correlated positively (r ranging from 0.71 to 0.93) with plasma concentrations of several essential and nonessential amino acids. These correlations suggest that individuals who ultimately will or will not achieve nitrogen equilibrium during very low calorie diets can be identified prior to dieting. These data are consistent with the hypothesis that individuals with higher initial protein flux and triiodothyronine levels are better able to adjust the balance between synthesis and degradation to attain nitrogen equilibrium during hypocaloric dieting.

Myocardial Mass in Morbidly Obese Patients and Changes with Weight Reduction

Cardiac weight was determined at autopsy in 27 morbidly obese, but otherwise healthy men (mean weight 168 kg) and women (mean weight 138 kg) who died suddenly, prior to, or shortly after gastric restriction operations for relief of obesity. They had lost no weight. Post-mortem examination revealed no cardiac or other pathology explaining the cause of death. Cardiac weight was also measured in 25 men and women of equivalent baseline weight and body mass index who, after operation, subsisted on a hypocaloric diet for 3-4 months after operation, but then died suddenly. Mean weight losses of this latter group were 45.8 kg in men and 32.9 kg in women. No cardiac abnormalities and no organic causes of death were found at autopsy. Decreases in heart weight were calculated. The baseline measurements demonstrated that cardiac weight in the healthy obese rose with increasingly severe obesity in both sexes, but the increase tended to lessen with more extreme obesity. The generally quoted figures of cardiac weight as a fraction of body weight are 0.043 and 0.040% for men and women, respectively. In the group of morbidly obese men, cardiac weight was 0.035% of body weight or 16% lower than predicted. In morbidly obese women, cardiac weight was 0.030% of body weight or 25% lower than predicted. In men, a 28% body weight reduction due to dietary restriction resulted in a proportionately similar 20% decrease in cardiac weight. In contrast, in women after a 27% loss of body weight, cardiac weight decreased only 5%. Severe dietary restriction with a drastic body weight loss did not result in a disproportionate decrease of cardiac weight in either sex, when final body weight had remained above or in the normal range.

Effects of oral and parenteral quinine on rats with ventromedial hypothalamic knife-cut obesity☆

The addition of quinine to the food reversed the obesity in rats with hypothalamic hyperphagia induced by knife cuts. Similarly, the injection of quinine into rats with hypothalamic knife cuts reduced food intake and body weight but the effects were smaller than those observed when quinine was added to the diet. Urinary quinine excretion was similar by the oral and parenteral routes. The food intake of the knife-cut animals receiving quinine gradually fell to the same level as in the sham-operated animals receiving quinine by either route. The weights of retroperitoneal fat pads were related to the weights of the animals and were reduced in the quinine-treated groups. Plasma insulin concentrations were significantly higher in the knife-cut animals and were reduced toward control levels by quinine treatment. Gluconeogenesis, measured by incorporation of radioactivity from labeled bicarbonate into glucose, was unaffected by treatment with quinine or by knife cuts. Lipogenesis from tritiated water in vivo was not different between treatment groups in the liver or retroperitoneal fat pads. However, in vivo lipogenesis was reduced in knife-cut rats fed ad libitum compared with quinine-treated rats. The response of lipogenesis to insulin in vitro was also not different between treatment groups. These data suggest that a major part of the reduction in food intake in hyperphagic rats eating a quinine-adulterated diet is due to postingestional events.