Macronutrient Self-selection Research Articles

Effect of glucagon in macronutrient self-selection: Glucagon-enhanced protein intake

The effect of glucagon on macronutrient selection was studied using rats. Continuous infusion of glucagon (5 ng/μl/h) into the lateral cerebral ventricle increased total caloric intake and protein selection, and decreased carbohydrate selection. Continuous infusion of glucagon subcutaneously induced similar changes. Since a hyperglycemic response to the intracranial injection of 2-deoxy-D-glucose (2DG) disappeared in rats either with bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) (17) or with acquired (21) and congenital (10) blindness, and bilateral lesions of the SCN eliminated the hyperglucagonemic response to the 2DG-injection (19), changes in the plasma glucagon concentration after 2DG injection were examined in acquired and congenital blind rats. Consequently, it was found that the hyperglucagonemic response to 2DG was not observed in those blind rats which lacked the hyperglycemic response. In those SCN-lesioned and blind rats lacking the hyperglucagonemic response to 2DG, the protein selection was lower, and carbohydrate selection tended to be higher, than those selections found in the control rats. Considering the neural connection between the retina and the SCN, these findings suggest that glucagon may have a stimulatory effect on protein intake and a suppressive one for carbohydrate intake; and that the SCN may be involved in such a regulatory mechanism of feeding behavior through controlling the blood glucagon level.

Glucocorticoids as modulators in the control of feeding

Three sets of experiments have been conducted that suggest that adrenal glucocorticoids play a role in the long-term control of intake and in dietary preferences. First, obesity is dependent upon glucocorticoid-modulated metabolic pathways. Surgical or pharmacological manipulations in obese animals that eliminate or diminish corticosterone activity result in levels of intake, meal patterns, macronutrient self-selection and weight gain that revert to levels seen in lean controls. Glucocorticoid replacement of adrenalectomized genetically obese Zucker rats restores the phenotypic expression of the obese rat's genetic heritage: increased weight gain, increased fat and total daily caloric intake and adiposity are restored in a dose-dependent fashion. Second, the increased fat intake observed subsequent to fasting in Sprague-Dawley rats is correlated with an increase in circulating corticosterone. Adrenalectomy blocks the fat specific refeeding response, and corticosterone treatment of adrenalectomized rats restores the increase in fat, carbohydrate and protein observed during refeeding. Third, humans suffering from Cushing's Disease have an increased preference for dietary fat. Weight-matched but disease-free obese controls show only slight increases in fat preference when compared to normal weight controls.

Fat-preferring rats consume more alcohol than carbohydrate-preferring rats

Rats with a genetic preference for alcohol (ETOH) have been found to consume more dietary fat then ETOH nonpreferring rats. We therefore hypothesized that rats selected on the basis of fat and carbohydrate (CHO) preferences would differ in ETOH intake. Patterns of macronutrient self-selection were determined by allowing rats to select diets from separate sources of CHO, fat and protein. Subsequently, CHO- and fat-preferring groups were formed. All rats were then returned to a lab chow diet and trained to drink ETOH (4-12%) during one hour of access per day. Food restriction was used only in the first three weeks of the procedure. On the final drinking sessions, water and ETOH were alternated on a daily basis. Fat-preferring rats consumed significantly more ETOH than water; CHO-preferring rats consumed approximately equal amounts of ETOH and water. Furthermore, fat-preferring rats consumed more ETOH than CHO-preferring rats. This study suggests that there may be a common mechanism underlying diet preference and oral intake of ETOH.

Exercise decreases fat selection in female rats during weight cycling

Weight cycling (weight loss and regain) increases fat intake in rats allowed to self-select a diet from protein, carbohydrate, and fat sources. This study reports the effects of exercise on macronutrient self-selection. Female Sprague-Dawley rats (5 mo old) self-selected their diet. After 3 wk, rats were assigned to one of the following three groups: ad libitum fed sedentary (Con), sedentary food restricted to 40% Con intake (R-Sed), or treadmill exercised (20 m/min, 1 h/day, 6 day/wk) food restricted to 40% Con intake (R-Ex). Food restriction was for 3 wk followed by 5 wk of refeeding. This was repeated for a second cycle. During restriction, body weight decreased by 30% in R-Sed and by 33% in R-Ex than in R-Sed, fat regain was greater in R-Sed. By week 3 of refeeding, total caloric consumption did not differ. However, fat selection increased in R-Sed (56% kcal) vs. R-Ex (30%) and Con (35%). Fat selection in R-Sed increased further during cycle 2 (73% kcal). Resting oxygen consumption decreased during food restriction in R-Sed and R-Ex. After refeeding, resting metabolic rate in R-Ex was significantly greater than in R-Sed. In conclusion, weight cycling increases dietary fat selection and adiposity. Exercise mitigates this effect.

The effect of dexamethasone-21-acetate on meal size, meal frequency and macronutrient self-selection in rats

In Experiment 1, the measurement of 24-hour food intake in two rats showed that treatment with dexamethasone-21-acetate (DEX) (0.5 mg/kg IP) produced a decrease in body weight which was at least partially due to a decrease in food intake (both meal frequency and meal size). In Experiment 2, the daily intake of three macronutrient sources was measured. These data showed that treatment with DEX (0.5 and 1.0 mg/kg IP) led to an acute increase in protein intake, a sustained decrease in fat intake and no change in carbohydrate consumption. We suggest that this change in macronutrient selection may be an adaptive response which serves to ameliorate some of the effects of DEX treatment.

Impact of acute corticosterone administration on feeding and macronutrient self-selection patterns.

Food intake, body weight, and meal patterns in rats are known to be specifically influenced by circulating corticosterone (CORT). The present study examined, in Sprague-Dawley rats, the role of CORT in the regulation of caloric intake and choice of macronutrients during specific periods of the light-dark cycle. Adrenalectomy (ADX) significantly attenuated the ingestion of all three macronutrients, namely, protein, carbohydrate, and fat, in different test periods of the light-dark cycle. This deficit was significantly stronger just before or during the early dark hours, compared with the light period, and it was immediately CORT reversible. During this same early dark period, the stimulatory effect of CORT (0.5 or 2.0 mg/kg sc) on total food intake in ADX animals was also significantly stronger than during the light period. At this time, the CORT-injected ADX animals consumed an even greater amount of total food intake than did the vehicle-injected sham-operated animals and showed a significant preference for carbohydrate, as opposed to no change or a decline in preference for protein or fat. These findings, in light of other evidence, suggest that CORT ensures and stabilizes the ingestion of all three macronutrients but, in particular, stimulates carbohydrate ingestion during the important feeding period at the dark onset when CORT levels normally peak. It is proposed that CORT may provide a critical signal, in conjunction with hypothalamic neurotransmitter systems, in the behavioral and metabolic regulation of body energy balance.

Weight cycling in female rats increases dietary fat selection and adiposity

The effect of repeated food restriction-refeeding (weight cycling) on macronutrient selection and adiposity was investigated in female Sprague-Dawley rats. Rats were maintained on ad lib macronutrient self-selection and were put on one of two types of restriction. One group was reduced to 75% of their body weight on restricted amounts of chow and a second group was given ad lib chow during the concurrent period and were voluntarily hypophagic. During refeeding on macronutrient self-selection, animals previously restricted selected a higher percentage of dietary fat, had larger adipose depots and plasma insulin values, and had lower heart weights both expressed in grams and as a percentage of body weight than non-restricted groups. This suggests that both severe and moderate periods of restriction may have negative health consequences.

Sucrose-induced hyperphagia and obesity in rats fed a macronutrient self-selection diet

Adult female rats were allowed to self-select their diet from separate sources of fat, protein, and carbohydrate (starch). Other rats were fed a composite diet that matched the nutrient composition chosen by the self-selecting rats (50% fat, 28% protein, 22% carbohydrate) or a low-fat, high-carbohydrate chow diet. Half of the rats in each diet condition were given access to a 32% sucrose solution for 30 days. Sucrose availability increased total caloric intake (≈20%) and body weight gain in all three groups compared to control groups not fed the sucrose solution. The selection animals compensated for their sucrose intake by reducing their fat intake, and to a lesser degree, their starch intake; protein intake was the least affected by sucrose availability. The selection rats consumed less sucrose than the chow-fed rats and displayed a smaller increase in weight, relative to controls, than the chow-fed rats. These differences were attributed to the high-fat intake of the selection animals since similar results were obtained with the rats fed the composite diet. In particular, both the selection and composite diets produced mild obesity in the absence of sucrose. The results demonstrate that sucrose-induced overeating and overweight is not an artifact of restraining the diet choices of rats to a pure sugar and a nutritionally complete diet.

Feeding and macronutrient selection patterns in rats: Adrenalectomy and chronic corticosterone replacement

To analyze further the role of corticosterone (CORT) in the control of feeding behavior, we examined the impact of adrenalectomy (ADX) and chronic CORT implants on the food intake and macronutrient self-selection patterns of adult male rats at different periods of the diurnal cycle. Consistent with a separate study of acute CORT injection in ADX rats (Kumar and Leibowitz, 1988), the present findings indicate that ADX significantly attenuated the rats' daily (24 hr) ingestion of all three macronutrients, namely, protein, carbohydrate and fat. However, food intake in the dark cycle, specifically during the first few hours after dark onset, was significantly more affected (−70%) than feeding in the later dark and light periods (−25%). Moreover, during this early dark time when circulating CORT level normally peaks, ADX appeared to have its strongest suppressive effect on carbohydrate ingestion. Chronic subcutaneous CORT implants in the ADX animals reversed these effects of surgery and generally restored the rats' eating patterns to that of the cholesterol-implanted SHAM animals. These findings suggest that CORT exerts a decisive influence on caloric intake, on the diurnal pattern of feeding, and on appetite for specific macronutrients. The impact of CORT on carbohydrate intake is apparent specifically during the active eating period, particularly at dark onset when endogenous CORT levels normally peak and carbohydrate is exhibited as the preferred macronutrient.

Serotonin manipulations and the structure of feeding behaviour

Experimental manipulations of 5-HT by central or peripheral procedures produce clear effects on food intake. Interpretation of these effects can be improved by monitoring changes in the behavioural structure of feeding and by designing experiments which adjust the contextual and temporal dimensions of feeding. Experimental techniques include micro-analysis of behaviour, macro-analysis of meal patterns, dietary self-selection of macro-nutrients, analysis of appetite and satiety sequences, appetitive and consummatory aspects of instrumental performance and dietary-induced hyperphagia. Using these procedures in conjunction with various pharmacological treatments including the administration of tryptophan, 5-hydroxy-tryptophan, 5-HT, re-uptake blockers, synaptic releasers, synthesis blockers, receptor blockers and others it has been demonstrated that 5-HT manipulations give rise to a specific constellation of changes in feeding parameters. The most prominent changes following peripheral or central (paraventricular nucleus) injections are a reduction in meal size and a curtailment of eating rate. These changes can be distinguished from those induced by other pharmacological treatments and are consistent with a modulation of the process of satiation and the state of satiety. Changes in feeding induced by 5-HT manipulations are not secondary to non-specific behavioural alterations.

Deficits in the control of food intake after hypothalamic paraventricular nucleus lesions

Noradrenergic mechanisms of the hypothalamic paraventricular nucleus (PVN) have been shown to play an important role in the stimulation of feeding To determine the influence of this nucleus in monitoring and controlling responses to physiological and pharmacological challenges, PVN electrolytic lesion rats were tested for their behavioral responsiveness to agents known to affect the α-2 noradrenergic system as well as release of corticosterone, and to short- and long-term periods of food deprivation. Discrete lesions of the PVN produced enhanced feeding, particularly of carbohydrate, in freely-feeding rats maintained on a macronutrient self-selection paradigm. Lesion rats demonstrated a behavioral deficit in food intake regulation (a decrease in carbohydrate ingestion) in response to 5-hr and 24-hr fasts, showed a disturbance in circadian feeding, and exhibited a dramatic decrease in circulating corticosterone. However, feeding in response to 2-deoxy-D-glucose and insulin remained intact, suggesting that noradrenergic receptors within the PVN are not involved in the mediation of glucoprivic-induced feeding.

Sham feeding, flavor associations and diet self-selection as indicators of feeding satiety or aversive effects of peptide hormones

We have attempted to develop a constellation of behaviors which show differential effects following the administration of putative satiety hormones (CCK-8, BBS, insulin) as opposed to effects seen following a toxin, such as LiCl. In the initial behavior assessed, sham feeding of differently paired, flavored milks (flavor paired with insulin, BBS or saline) was carried out. Male adult Sprague-Dawley rats which sham fed milk flavors paired with 16 μg/kg BBS showed a significant aversion of that flavor in a two-bottle taste test (compared to saline-paired flavors, p<0.001) but a significant preference for flavored milk paired with 0.4 and 0.75 U insulin/rat. Lower dosages of BBS (4 and 8 μg/kg) and insulin (0.1 U/rat) showed no significant aversion or preference when compared to saline. The second behavioral paradigm evaluated the effects of the hormones CCK-8 and BBS and the toxin, LiCl, upon self-selection of pure macronutrients. While CCK-8 reduced intake of calories by significantly lowering ingestion/selection of fats (55%, p<0.01 compared to saline, control injections) and carbohydrates (50%, p<0.01), LiCl and BBS reduced calories by decreasing selection of primarily proteins (LiCl—49%, p<0.03; BBS—63% at 4 μg/kg and 80% at 8 μg/kg, both p<0.025). In both paradigms then, BBS at doses sufficient to significantly reduce sham intake or suppress caloric ingestion in a self-selection paradigm produced behavioral effects most similar to those observed following the injection of a toxin, LiCl, rather than effects seen following other various putative satiety signals.

Macronutrient self-selection in three forms of hypothalamic obesity.

Adult female rats were adapted to a macronutrient self-selection regimen which allowed them ad libitum access to separate sources of protein, carbohydrate, and fat. The rats were then given either ventromedial hypothalamic (VMH) lesions, paraventricular hypothalamic (PVH) lesions, parasagittal knife cuts through the medial hypothalamus (CUT), or sham lesions and their macronutrient selection was studied for 60 days. Following surgery the VMH, PVH, and CUT rats overate and became obese compared with controls. The hyperphagias of the three groups were similar, although the CUT group gained more weight than did the PVH and VMH groups. All groups overate primarily by increasing their carbohydrate intake. The VMH and CUT groups, in addition, increased their protein intake such that their percent protein intake remain unchanged. The PVH group failed to increase its absolute protein intake and thus decreased its percent protein intake. Except for a transient increase, fat consumption was not affected by the lesions or knife cuts. During the 2nd postoperative mo (static phase) the total caloric intakes and the carbohydrate intakes of the VMH, PVH, and CUT groups returned to near normal levels. Rats with misplaced PVH lesions displayed minimal hyperphagia and failed to outgain controls but yet showed the same altered macronutrient selection pattern as did rats with obesity-inducing PVH lesions. Measurements of resting insulin levels at the end of the experiment revealed hyperinsulinemia in the VMH and CUT groups but normal insulin values in the PVH group. These results demonstrate that VMH lesions, PVH lesions, and medial knife cuts produce similar hyperphagia syndromes associated with carbohydrate-specific overeating, but that they differentially affect protein selection and resting insulin levels.

Dorsomedial hypothalamic hypophagia: Self-selection of diets and macronutrients, efficiency of food utilization, “stress eating”, response to high-protein diet and circulating substrate concentrations

Compared to sham-operated controls, male weanling rats with bilateral dorsomedial hypothalamic lesions (DMNL rats) showed hypophagia, reduced ponderal and linear growth, normal body composition and decreased efficiency of food utilization (EFU) two weeks after the hypothalamic operation. Subsequently, all animals were given a choice between three equicaloric diets with different macronutrient content for a period of 31 days. DMNL rats selected significantly less high-fat (HFD) and high-protein (HPD) diet than controls, but in percent of total intake, they selected only less from the HPD. DMNL rats consumed less of all three macronutrients than the controls, but in percent of total calories consumed, their intake was comparable to that of the controls; the EFU during this period was normal. Tail pinch (TP) stress did not result in hyperphagia, nor in a macronutrient choice different from the non-TP rats. However, TP caused reduced EFU and linear growth irrespective of hypothalamic damage, suggesting a stress response. During the 25-day availability of a HPD (43.2%), both DMNL rats and controls ate amounts of macronutrients comparable to the self-selection experiment. Although the DMNL rats were hypophagic in comparison with the controls, they ate more protein than in the self-selection experiment because of the higher protein content of the diet. Thus, DMNL rats will eat more protein when other macronutrients are limited. In both fed and 48h-fasted rats, there was no significant alteration in plasma glucose, glycerol, and total protein that could be related to the DMN lesions. It is concluded that the DMNL rat, despite its dramatically reduced size and energy intake, has not lost the capacity to select macronutrients for normal growth and health within the framework of its reduced somatic-metabolic potential.

Associations among food and protein intake, serine dehydratase, and plasma amino acids.

Associations among food and protein intake, serine dehydratase, and plasma amino acids.