Dopamine and serotonin VMN release is related to feeding status in obese and lean Zucker rats

Study of neurotransmitter role in food intake regulation in a leptin signaling deficient model, such as the Zucker rat, would benefit in the understanding of mechanisms of human obesity, in which leptin resistance is a common syndrome. We studied dopamine (DA) and serotonin (5-HT) concentrations in vivo in the ventromedial nucleus (VMN) of the hypothalamus, as they relate to eating after food deprivation in obese and lean 9-week-old male Zucker rats. DA and 5-HT concentrations were measured by HPLC via microdialysis before and during refeeding in 24-h food-deprived rats. Before food was provided, mean baseline DA and 5-HT levels were lower in obese than in lean rats (9.2 +/- 0.9 vs 15.1 +/- 1.9 pg/10 microl, p < 0.01, and 0.68 +/- 0.05 vs 1.17 +/- 0.02 pg/10 microl, p < 0.001, respectively). Food intake was accompanied by a decrease in DA levels in both obese and lean rats to 64% (p < 0.01) and 65% (p < 0.02) of their baseline levels respectively. 5-HT levels were significantly increased during eating by 41% in obese and 35% in lean rats (p < 0.01) from the baseline levels. Thus in obese rats with altered leptin signaling we found an unaltered pattern of DA and 5-HT release associated with food deprivation and refeeding, but with presence of their low levels. This points to an impaired postsynaptic monoaminergic action to produce an adequate metabolic response in obese Zucker rats in response to feeding state.     

Meal-induced changes in extracellular 5-HT in medial hypothalamus of lean (Fa/Fa) and obese (fa/fa) Zucker rats

Hypothalamic serotonin (5-HT) is involved in appetite regulation and sympathetic stimulation of thermogenesis. This study tested the hypothesis that the enhanced energetic efficiency of obese Zucker rats involves blunted serotonergic release within the medial hypothalamus (MH). We used microdialysis and HPLC-EC to measure dynamic changes in extracellular 5-HT levels in the MH of 10-13-week-old male lean (Fa/Fa) and obese (fa/fa) Zucker rats before and after a meal. No differences were noted in basal levels of 5-HT between lean and obese rats. Consistent with the suggestion that hypothalamic 5-HT plays a physiological role in feeding, extracellular 5-HT levels increased significantly in both lean and obese rats given a meal. This increase was observed in the 20 min interval in which they ate the 8.1 kcal meal and remained for an additional 60 min. The net release of 5-HT during the meal interval was comparable in the lean (1.46+/-0.38 fmol/microl) and obese (1.21+/-0.82 fmol/microl) rats. However, the 5-HT levels of the leans (1.80+/-0.29 fmol/microl) plateaued in the next 20 min interval, whereas they continued rising (2.74+/-0.53 fmol/microl) in obese rats and were significantly higher than those in the leans during the 40 and 60 min intervals after the meal was presented. This resulted in a total net release during the meal plus the next three 20 min intervals that was significantly higher in obese (9.83+/-1.16 fmol/microl) than in lean (5.59+/-0.85 fmol/microl) rats. Thus, the enhanced energetic efficiency of the obese Zucker rats may not be associated with attenuated serotonin release in response to a meal. Rather their enhanced release of 5-HT in the MH may reflect compensatory mechanisms for the elevated orexigen NPY, the reduction in meal-induced CCK release, and/or a functional resistance to 5-HT.     

Role of glucagon in the control of food intake in zucker obese and lean rats

Although there is strong evidence for glucagon's role in the control of food intake, the essentiality of this role remains in question. In several experiments the feeding responses to glucagon and glucagon antisera were investigated in both Zucker and Sprague-Dawley rats. Intraperitoneal injection of 400 micrograms/kg glucagon decreased 30-min food intake 18% (p less than 0.01) in Zucker lean rats and increased 30-min food intake 16% (NS) in Zucker obese rats, suggesting obese rats are less sensitive. In Sprague-Dawley rats the same dose decreased first meal size 28% (p less than 0.01), indicating that they were more sensitive than Zucker lean rats. Intraperitoneal injection of 400 micrograms/kg glucagon increased plasma glucagon concentrations in the vena cava and the tail vein 150-fold and 10-fold, thus, superphysiological doses may be required to elicit satiety. In contrast, administration of a glucagon antisera increased food intake of Zucker rats for up to 6 hr and increased meal size for 5 hr. The findings suggest that glucagon's role in control of food intake in Zucker obese and lean rats is similar, but the superphysiological glucagon changes which occur with exogenous administration indicate that glucagon may only indirectly elicit satiety.     

Meal-induced changes in extracellular 5-HT in medial hypothalamus of lean (Fa/Fa) and obese (fa/fa) Zucker rats

Hypothalamic serotonin (5-HT) is involved in appetite regulation and sympathetic stimulation of thermogenesis. This study tested the hypothesis that the enhanced energetic efficiency of obese Zucker rats involves blunted serotonergic release within the medial hypothalamus (MH). We used microdialysis and HPLC–EC to measure dynamic changes in extracellular 5-HT levels in the MH of 10–13-week-old male lean (Fa/Fa) and obese (fa/fa) Zucker rats before and after a meal. No differences were noted in basal levels of 5-HT between lean and obese rats. Consistent with the suggestion that hypothalamic 5-HT plays a physiological role in feeding, extracellular 5-HT levels increased significantly in both lean and obese rats given a meal. This increase was observed in the 20 min interval in which they ate the 8.1 kcal meal and remained for an additional 60 min. The net release of 5-HT during the meal interval was comparable in the lean (1.46±0.38 fmol/μl) and obese (1.21±0.82 fmol/μl) rats. However, the 5-HT levels of the leans (1.80±0.29 fmol/μl) plateaued in the next 20 min interval, whereas they continued rising (2.74±0.53 fmol/μl) in obese rats and were significantly higher than those in the leans during the 40 and 60 min intervals after the meal was presented. This resulted in a total net release during the meal plus the next three 20 min intervals that was significantly higher in obese (9.83±1.16 fmol/μl) than in lean (5.59±0.85 fmol/μl) rats. Thus, the enhanced energetic efficiency of the obese Zucker rats may not be associated with attenuated serotonin release in response to a meal. Rather their enhanced release of 5-HT in the MH may reflect compensatory mechanisms for the elevated orexigen NPY, the reduction in meal-induced CCK release, and/or a functional resistance to 5-HT.     

Effects of repeated administration of mifepristone and 8-OH-DPAT on expression of preproneuropeptide Y mRNA in the arcuate nucleus of obese Zucker rats.

Neuropeptide Y (NPY) is an important hypothalamic regulator of feeding behavior. In this study we have investigated the regulation of the expression of preproNPY mRNA in male obese and lean Zucker rats by in situ hybridization. These animals represent a model of genetic obesity with hyperphagia, hyperinsulinemia and altered endocrine functions. Obese Zucker rats, treated for 12 days with 0.9% saline, had about 210% higher level of basal preproNPY mRNA expression in the arcuate nucleus when compared to their lean littermate controls. Repeated administrations of 8-hydroxy-dipropylaminotetralin (8-OH-DPAT), a serotonergic 5-HT1A agonist, or mifepristone, a glucocorticoid receptor antagonist, did not modify the basal expression of preproNPY mRNA in the Zucker phenotypes. The 8-OH-DPAT treatment significantly reduced hyperinsulinemia in obese Zucker rats without changing plasma glucose levels. The mifepristone treatment significantly increased plasma corticosterone levels in lean animals, but not in obese animals. The present study demonstrates enhanced expression of preproNPY mRNA in the arcuate nucleus in obese Zucker rats suggesting an involvement of NPY in the pathophysiology of the hyperphagic syndrome and genetically determined obesity in Zucker rats. Neither the antagonism of glucocorticoid receptors by mifepristone, nor repeated treatment with 8-OH-DPAT resulting in reduced insulin levels in obese Zucker rats, modified the basal expression of preproNPY mRNA in the arcuate nucleus.     

Neuronal activation and corticotropin‐releasing hormone expression in the brain of obese (fa/fa) and lean (fa/?) Zucker rats in response to refeeding

The present study was conducted to investigate the pattern of neuronal activation and corticotropin‐releasing hormone (CRH) expression in fed, food deprived and refed lean (Fa/?) and obese (fa/fa) Zucker rats. The pattern of neuronal activation was studied by measuring the expression of the immediate‐early gene c‐fos. Expression of c‐fos and CRH mRNA was determined by in situ hybridization histochemistry. In both lean and obese rats, one hour of refeeding led to a transient increase in c‐fos mRNA levels which was detected in the paraventricular hypothalamic nucleus (PVH), the dorsomedial hypothalamic nucleus, the supraoptic nucleus, the paraventricular thalamic nucleus, the central nucleus of amygdala (CeA), the lateral and medial parabrachial nuclei, the nucleus of the solitary tract, and the area postrema. In addition, refeeding led to strong activation of the arginine‐vasopressin neurons located in the magnocellular part of the PVH. Following 24 h of food deprivation, CRH expression in the parvocellular division of the PVH was significantly higher in obese rats compared to lean animals. During refeeding, PVH CRH mRNA levels in obese rats decreased to reach control values. The decrease in CRH expression in obese rats was accompanied by the alleviation of the hypercorticosteronemia that characterized obese Zucker rats. CRH mRNA levels in the central nucleus of the amygdala were significantly higher in lean rats than in obese animals, when the rats were fed ad libitum During food deprivation, CeA CRH mRNA levels decreased in lean rats and gradually returned to predeprivation values during refeeding. In refed obese rats, CeA levels of CRH mRNA were higher than those of ad libitum fed or food‐deprived obese mutants. In the perifornical region of the lateral hypothalamic area (LHA), the expression of CRH mRNA rose significantly in response to refeeding in lean rats, but not in obese animals. Following the first hour of refeeding, the number of neurons expressing CRH mRNA in the LHA in lean rats almost doubled. The present results demonstrate that refeeding has a stimulating effect in obese Zucker rats in a pattern of activation similar to that seen in lean Fa/? rats. They also demonstrate differences in CRH expression between Fa/? and fa/fa rats after refeeding. The most apparent of these differences was seen in the lateral hypothalamus in which refeeding failed to up‐regulate CRH expression in obese rats.     

Eating induced rise in LHA-dopamine correlates with meal size in normal and bulbectomized rats

Dopaminergic function in the lateral hypothalamic area (LHA) is important for processing intrinsic and extrinsic feeding related information. Brain microdialysis was used to examine if dopamine release in the LHA correlates with meal size in normal and bulbectomized rats. Food-deprived bulbectomized rats ate significantly less food (1.7 ± 0.1 g) than food-deprived sham operated rats (3.1 ± 0.5 g, p < 0.05), accompanied by a lesser increase in LHA-dopamine release (150.6 ± 4.9% vs. 195.1 ± 13.9, p < 0.02). LHA-dopamine release was significantly higher in rats which ate a full meal (2.9 ± 0.1 g) than in rats which ate half a meal (1.5 ± 0.1 g, p < 0.05), being 155.9 ± 7.8% vs. 131.0 ± 4.9% (p < 0.05) in food-deprived normal rats. Data suggest that dopamine release in the LHA correlates to the quantity of food consumed during a meal.     

Decreased striatal D2 dopamine receptors in obese Zucker rats: changes during aging.

The specific binding of [3H]YM-09151-2 was used to investigate the possible differences in age-associated changes in striatal D2 dopamine (DA) receptor properties in genetically obese (fa/fa) Zucker rats and their lean (Fa/?) littermates. The maximal binding sites (Bmax) of D2 DA receptors was found to decline with age in both obese and lean rats; the rate of decline in receptor Bmax was slightly higher in lean than obese rats. However, the Bmax of D2 DA receptor in 6-, 12- and 18-month-old obese rats was significantly lower compared to the age-matched lean rats. These data indicate that obesity decreases the number of striatal D2 DA receptors without affecting the rate at which receptor number decreases with age.     

Zucker obese rats: defect in brain histamine control of feeding

Manipulation of hypothalamic histamine produced different effects on feeding between the Zucker obese (fa/fa) and their lean littermate rats (Fa/−). Infusion of a histamine H₁-receptor antagonist into the third cerebroventricle elicited feeding in the lean and Wistar King A rats, but it did not affect feeding in the obese rats. To enhance hypothalamic neuronal histamine, thioperamide, an H₃-receptor antagonist, was similarly infused. The lean and Wistar rats decreased their food intake after the infusion, but thioperamide produced no significant effect on feeding in the obese rats. Infusion of histamine into the third cerebroventricle mimicked the effects of thioperamide on feeding: reduction of food intake in the lean and Wistar rats, but no significant change in the obese rats. Hypothalamic histamine of the obese rats (0.430 nmol/g) was significantly lower than the lean (1.209 nmol/g) and Wistar rats (4.838 nmol/g). The histamine concentration of the cerebral cortex in the obese rats was also lower than the non-obese animals. The results indicate that the feeding abnormality of Zucker obese rats may be at least due to disturbance of histamine suppressive signals both at presynaptic and postsynaptic levels.     

Down-regulation of orexin gene expression by severe obesity in the rats: studies in Zucker fatty and zucker diabetic fatty rats and effects of rosiglitazone

Orexins (hypocretins) are lateral hypothalamic neuropeptides implicated in regulating feeding and the sleep-wake cycle. To study their possible relevance to obesity and diabetes, we measured hypothalamic prepro-orexin mRNA levels in obese, normoglycemic Zucker fatty (fa/fa) and in hyperglycemic, non-obese Zucker diabetic fatty (ZDF) rats. Hypothalamic prepro-orexin mRNA concentrations in Zucker fatty rats were 31% lower than those in lean controls (0. 69+/-0.06 vs. 1.00+/-0.10 arbitrary units, P<0.05), but did not differ between ZDF diabetic rats and non-diabetic controls. Treatment of ZDF diabetic rats with rosiglitazone (1 or 3 mg/kg body weight daily for 13 weeks) normalized plasma glucose and significantly reduced plasma insulin, while leptin levels were 67% higher than in untreated ZDF rats (20.2+/-0.5 vs. 12.1+/-2.5, P<0. 001). Rosiglitazone treatment markedly enhanced weight gain compared with untreated ZDF rats (final weight 732+/-13 g vs. 409+/-13 g, P<0. 001) even though they were restricted to the same food intake. Rosiglitazone-treated ZDF rats had significantly lower hypothalamic prepro-orexin mRNA levels (0.68+/-0.07 arbitrary units) than both non-diabetic lean controls (1.00+/-0.10, P=0.02) and untreated diabetics (1.03+/-0.14, P=0.03). Our data suggest that prepro-orexin gene expression may be suppressed by substantial weight gain. Obesity-related signals that might mediate this effect have not been identified, but plasma leptin, insulin and glucose are not obviously involved.     

Developmental aspect of differences in hypothalamic preproneuropeptide y messenger ribonucleic Acid content in lean and genetically obese zucker rats

The genetically obese Zucker rat is a well characterized model of early onset human obesity. Many of the endocrine and metabolic abnormalities of obese animals are common to other strains of genetically obese animals as well as morbidly obese humans. Neuropeptide Y (NPY), a potent orexigenic agent, was recently found to be elevated in adult obese animals compared to their lean littermates. In this study we first examined hypothalamic expression of preproNPY mRNA, using solution hybridization/ nuclease protection analysis, in phenotypically-matched, i.e. lean or obese, immature (5-week-old) and mature (33-week-old) animals. Although changes were not statistically different, a trend toward decreased hypothalamic preproNPY mRNA levels was detected in both lean and obese mature animals. We next compared hypothalamic preproNPY mRNA levels between age-matched lean and obese animals at 5, 14 and 33 weeks of age and found elevated preproNPY mRNA levels in obese rats at all three ages. These data suggest that increased levels of hypothalamic NPY are an early manifestation of the obese phenotype and may, therefore, contribute to hyperphagia and increased weight gain in obese Zucker rats.     

Striatal dopamine metabolism is differentially affected by insulin according to the genotype in Zucker rats: a microdialysis study.

The genetically obese Zucker rat presents several abnormalities related to insulin and brain monoamines, which may play a role in its impaired regulation of food intake and body weight. In a previous study, the possible insulin-monoamine interplay was investigated by measuring brain monoamine and metabolite levels in the three genotypes of the Zucker strain. In addition to the expected results, insulin had a particular effect on striatal dopamine (DA) release, regardless of ponderal status and genotype. We further investigated this point in the present study, using the brain microdialysis technique in the striatum. Lean homozygous Fa-Fa rats responded as expected to insulin with regard to striatal DA release, with increases in DA and 3-methoxy-tyramine levels and decreases in dihydroxyphenylacetic acid and homovanillic acid. Lean heterozygous Fa-fa rats showed a very specific response profile, with decreases in all dopaminergic parameters, suggestive of an effect on DA synthesis rather than DA release. This further emphasizes the marked differences between homozygous and heterozygous lean rats. The obese fa-fa rats clearly fell into two populations. The first showed a profile of response to insulin similar to that of the lean Fa-fa rats, in keeping with the disturbances related to the "fa" gene. The second showed an increase in all the dopaminergic parameters. This pattern of response was, however, different from that of the Fa-Fa rats. These opposing responses in the two obese populations did not reflect differences in the blood glucose response to insulin. One explanation is that 16 wk may be a critical transition period in the development of genetic obesity, with regard to brain monoamine disturbances and the response to insulin.     

Central and peripheral dysregulation of melanin-concentrating hormone in obese Zucker rats

Melanin concentrating hormone (MCH) is a peptide synthesized in the lateral hypothalamus which stimulates food ingestion and leptin secretion in rodents. In this experiment, we measured the expressions of MCH as well as of its receptor (SLC-1) in the hypothalamus of obese hyperphagic and lean Zucker rats by quantitative real time RT-PCR. MCH mRNA expression in the obese rats was significantly increased by a factor of five (P<0.01) whereas expression of SLC-1 was decreased by more than 50% (P<0.05). Circulating levels of leptin and MCH were increased in the plasma of obese Zucker rats when compared to lean rats (38-fold and 1.7-fold, respectively, P<0.001 and P<0.01). However, individual MCH levels were not directly correlated to leptin levels in the lean (functional leptin receptor) or in the obese (non-functional leptin receptor) Zucker rats. These results indicate that the absence of leptin signaling in rats is associated with an increased hypothalamic expression and circulating release of MCH, contributing to their obesity syndrome.     

Effects of fluoxetine administration on hypothalamic melanocortin system in obese Zucker rats

The aim of the present work was to study the potential involvement of melanocortin system in the anorectic mechanism of fluoxetine, a selective serotonin reuptake inhibitors, in obese Zucker rats. Male obese Zucker (fa/fa) rats were administered fluoxetine (10 mg/kg; i.p.) daily for two weeks. The control group was given 0.9% NaCl solution. RT-PCR for pro-opiomelanocortin (POMC), Agouti gene related peptide (AgRP) and melanocortin receptor 4 (MC4-R) in the hypothalamus, as well as regional immunostaining for alpha-melanocyte stimulating hormone (alpha-MSH) and MC4-R were carried out. Fluoxetine administration increased POMC expression and reduced MC4-R expression in the hypothalamus, without changes in AgRP mRNA levels. Moreover, an increase in the numbers of alpha-MSH positively immunostained neural cells in the hypothalamic arcuate nucleus (ARC), as well as a significant decrease in the numbers of neural cells positively immunostained for MC4-R in the paraventricular nucleus (PVN), without changes in lateral hypothalamic area (LHA), were observed. These results suggest the involvement of alpha-MSH in central fluoxetine anorectic action.     

Parasympathetic response to acute stress is attenuated in young Zucker obese rats

We compared arterial blood pressure (BP) and heart rate (HR) control in 9- to 11-week old obese Zucker rats (n=10; weight=452+/-45 g, average+/-SD) to age-matched, lean Zucker animals (n=13; weight=280+/-46 g). BP was measured by indwelling catheter. Baseline pressure was 113.1+/-7.0 mm Hg in the lean vs. 111.7+/-5.6 in the obese rats (NS). Baseline HR was 413+/-43 in the lean vs. 422+/-22 bpm in the obese animals (NS). Rats were classically conditioned by following a 15-second tone (CS+) with a 0.5-second tail shock. There were no between-group differences in the BP response to CS+. Conversely, heart rate (HR) decreased significantly (p<0.05) more during the last 10 s of the tone in the lean group (-46.0+/-21.5 bpm) vs. the obese (-17.8+/-21.7 bpm). This bradycardia was blocked by atropine. Finally, the change in HR divided by the change in arterial BP (DeltaHR/DeltaBP) following an intravenous bolus of phenylephrine (PE; 5 microg/kg) and following sodium nitroprusside (NP; 5 microg/kg) was determined. The DeltaHR/DeltaBP following PE was smaller in the obese (n=6; -1.36+/-0.60) vs. lean (n=5; -2.80+/-0.92); there was no difference in the response following NP. These data indicate that the BP response to a behavioral challenge did not differ in the obese rat vs. the lean animal, but that the obese subjects had an attenuated parasympathetic response to the stress, probably secondary to alterations in baroreflex function.     

Dopamine transporter mRNA is increased in the CNS of Zucker fatty (fa/fa) rats

The obese Zucker fa/fa rat is characterized by hyperinsulinemia, obesity, and altered monoamine metabolism in the central nervous system (CNS). It has been proposed that the changes in monoamine metabolism may contribute to the metabolic pathophysiology of these animals. Because it has been reported that insulin may regulate the catecholamine reuptake transporters, which terminate monoaminergic synaptic signaling, in the present study we tested whether messenger ribonucleic acid (mRNA) levels for the noradrenergic (NE) or dopaminergic (DA) transporters were altered in obese fa/fa vs. lean Fa/Fa Zucker rats. We found significantly elevated DA transporter levels in both the ventral tegmental area/substantia nigra pars compacta (VTA/SNc) and zona incerta (ZI) of obese Zucker fa/fa rats (164 ± 24% of control levels, p = .024; and 316 ± 61% of control levels, p = .019, respectively). Measurement of mRNA for tyrosine hydroxylase (TH), the rate-limiting enzyme for NE and DA synthesis revealed no effect of the fa gene in either NE or DA neurons. These findings suggest that increased DA clearance, and perhaps decreased DA signaling, may occur in the obese Zucker fa/fa rat.     

Intraduodenal infusions of fat inhibit sham feeding in zucker rats

Intraduodenal infusions of Intralipid in concentrations of 0.125 kcal/ml to 1 kcal/ml inhibited sham feeding of lean and obese Zucker rats significantly. The inhibitory potency of the fat infusions on sham feeding in both genotypes was a function of the concentration of Intralipid infused. The inhibition of sham feeding by Intralipid infusions was accompanied by the specific sequence of behaviors that characterizes satiety. Evidence supporting differential effectiveness of intraduodenal fat in producing satiety in obese and lean rats was equivocal. A conservative interpretation is that obese rats are not less sensitive than leans to the satiating potency of intraduodenal fat. We conclude that previously reported differences in the satiating potency of fats for obese and lean Zucker rats are not likely to be mediated by small intestinal mechanisms.     

Decreased striatal D2 dopamine receptors in obese Zucker rats: changes during aging

The specific binding of [³H]YM-09151-2 was used to investigate the possible differences in age-associated changes in striatal D₂ dopamine (DA) receptor properties in genetically obese (fa/fa) Zucker rats and their lean3(Fa/?) littermates. The maximal binding sites (B_max) of D₂ DA receptors was found to decline with age in both obese and lean rats: the rate of decline in receptor B_max was slightly higher in lean than obese rats. However. the B_max of D₂ DA receptor in 6-, 12- and 18-month-old obese rats was significantly lower compared to the age-matched lean rats. These data indicate that obesity decreases the number of striatal D₂ DA receptors without affecting the rate at which receptor number decreases with age.     

Brown fat thermogenesis and its role in the development of obesity

The role of brown fat thermogenesis in the development of obesity is considered from a number of perspectives. In adult rats, the impact of scapular brown fat lipectomy on carcass fat accretion was examined in three different rodent models: the Zucker lean (Fa/-) rat which is relatively resistant to obesity, the Zucker obese (fa/fa) rat which is characterized by a particularly severe form of hyperplastic obesity and the Osborne Mendel rat which remains lean on a standard pelleted diet but readily becomes obese on a palatable high fat diet. The consequences of brown fat lipectomy varied from no effect on carcass white fat accretion in Zucker Fa/- lean rats to a significant increase in adiposity in the Zucker fatty fa/fa relative to their respective sham-operated controls. The effect of the Osborne Mendel rat was intermediate between the Fa/- and the fa/fa. The results point to the importance of genetic background with respect to the impact of brown fat lipectomy on the development of white fat adiposity. In the developing Zucker rat at 2 and 8 days of age, in vivo evidence is presented to support the concept that brown fat thermogenesis is attenuated in the fatty fa/fa preobese pup. In animals of the fatty fa/fa genotype, maximum oxygen consumption in response to acute cold exposure was lower than in lean pups of the Fa/Fa genotype. Moreover, at 8 days of age, the rectal temperature of the cold-exposed fa/fa pups fell more precipitously than did that of the lean during the period of cold exposure.(ABSTRACT TRUNCATED AT 250 WORDS)