Weight-sparing effect of insulin detemir: a consequence of central nervous system-mediated reduced energy intake?

Insulin therapy is often associated with adverse weight gain. This is attributable, at least in part, to changes in energy balance and insulin's anabolic effects. Adverse weight gain increases the risk of poor macrovascular outcomes in people with diabetes and should therefore be mitigated if possible. Clinical studies have shown that insulin detemir, a basal insulin analogue, exerts a unique weight-sparing effect compared with other basal insulins. To understand this property, several hypotheses have been proposed. These explore the interplay of efferent and afferent signals between the muscles, brain, liver, renal and adipose tissues in response to insulin detemir and comparator basal insulins. The following models have been proposed: insulin detemir may reduce food intake through direct or indirect effects on the central nervous system (CNS); it may have favourable actions on hepatic glucose metabolism through a selective effect on the liver, or it may influence fluid homeostasis through renal effects. Studies have consistently shown that insulin detemir reduces energy intake, and moreover, it is clear that this shift in energy balance is not a consequence of reduced hypoglycaemia. CNS effects may be mediated by direct action, by indirect stimulation by peripheral mediators and/or via a more physiological counter-regulatory response to insulin through restoration of the hepatic-peripheral insulin gradient. Although the precise mechanism remains unclear, it is likely that the weight-sparing effect of insulin detemir can be explained by a combination of mechanisms. The evidence for each hypothesis is considered in this review.

Metabolic vs. hedonic obesity: a conceptual distinction and its clinical implications.

Body weight is determined via both metabolic and hedonic mechanisms. Metabolic regulation of body weight centres around the 'body weight set point', which is programmed by energy balance circuitry in the hypothalamus and other specific brain regions. The metabolic body weight set point has a genetic basis, but exposure to an obesogenic environment may elicit allostatic responses and upward drift of the set point, leading to a higher maintained body weight. However, an elevated steady-state body weight may also be achieved without an alteration of the metabolic set point, via sustained hedonic over-eating, which is governed by the reward system of the brain and can override homeostatic metabolic signals. While hedonic signals are potent influences in determining food intake, metabolic regulation involves the active control of both food intake and energy expenditure. When overweight is due to elevation of the metabolic set point ('metabolic obesity'), energy expenditure theoretically falls onto the standard energy-mass regression line. In contrast, when a steady-state weight is above the metabolic set point due to hedonic over-eating ('hedonic obesity'), a persistent compensatory increase in energy expenditure per unit metabolic mass may be demonstrable. Recognition of the two types of obesity may lead to more effective treatment and prevention of obesity.

Note: ion source design for ion trap systems.

A small plasma (glow discharge) based ion source and circuit are described in this work. The ion source works by producing a high voltage pulsed discharge between two electrodes in a pressure range of 50-100 mTorr. A third mesh electrode is used for ion extraction. The electrodes are small stainless steel screws mounted in a MACOR ionization chamber in a linear arrangement. The electrode arrangement is driven by a circuit, design for low power operation. This design is a proof of concept intended for applications on small cylindrical ion traps.

Characterization system for research on energy storage capacitors.

In this work a characterization system for high energy-density capacitors is described and demonstrated. Capacitors are being designed using thin-film technology in an attempt to achieve higher energy-density levels by operating the devices at a high voltage. These devices are fabricated from layers of 100 nm aluminum and a layer of polyvinylidene fluoride-hexafluoropropylene on a polyethylene naphthalate plastic substrate. The devices have been designed to store electrical charge at up to 200 V. Characterizations of these devices focus on the measurement of capacitance vs bias voltage and temperature, equivalent series resistance, and charge/discharge cycles. For the purpose of the characterization of these capacitors, an electronic charge/discharge interface was designed and tested.

The consequences of chromosomal aneuploidy on gene expression profiles in a cell line model for prostate carcinogenesis.

Here we report the genetic characterization of immortalized prostate epithelial cells before and after conversion to tumorigenicity using molecular cytogenetics and microarray technology. We were particularly interested to analyze the consequences of acquired chromosomal aneuploidies with respect to modifications of gene expression profiles. Compared with nontumorigenic but immortalized prostate epithelium, prostate tumor cell lines showed high levels of chromosomal rearrangements that led to gains of 1p, 5, 11q, 12p, 16q, and 20q and losses of 1pter, 11p, 17, 20p, 21, 22, and Y. Of 5700 unique targets on a 6.5K cDNA microarray, approximately 3% were subject to modification in expression levels; these included GRO-1, -2, IAP-1,- 2, MMP-9, and cyclin D1, which showed increased expression, and TRAIL, BRCA1, and CTNNA, which showed decreased expression. Thirty % of expression changes occurred in regions the genomic copy number of which remained balanced. Of the remainder, 42% of down-regulated and 51% of up-regulated genes mapped to regions present in decreased or increased genomic copy numbers, respectively. A relative gain or loss of a chromosome or chromosomal arm usually resulted in a statistically significant increase or decrease, respectively, in the average expression level of all of the genes on the chromosome. However, of these genes, very few (e.g., 5 of 101 genes on chromosome 11q), and in some instances only two genes (MMP-9 and PROCR on chromosome 20q), were overexpressed by > or =1.7-fold when scored individually. Cluster analysis by gene function suggests that prostate tumorigenesis in these cell line models involves alterations in gene expression that may favor invasion, prevent apoptosis, and promote growth.

Sexual dimorphism in circulating leptin concentrations is not accounted for by differences in adipose tissue distribution.

BACKGROUND: Circulating concentrations of leptin normalized to total adipose tissue mass are significantly greater in females than in males. Rates of leptin expression (per gram of adipose tissue) are significantly greater in subcutaneous (SAT) than visceral (VAT) adipose tissue and the relative amount of fat stored as SAT vs VAT is significantly greater in pre-menopausal females than in males. Gender-related differences in the relative amounts of SAT and VAT may account for the greater circulating leptin concentration relative to fat-mass in females than males. METHODS: We examined body composition and anatomic fat distribution by dual energy X-ray-absorptiometry (DEXA) and magnetic resonance imaging (MRI), and post-absorptive circulating concentrations of leptin and insulin in 58 subjects (26 females, 32 males). Stepwise multiple linear regression analyses, treating gender as a dichotomous variable, were performed to determine inter-relationships among leptin concentrations and insulin concentrations, VAT and SAT. RESULTS: Body composition by DEXA and MRI were highly correlated (r(2)=0.97, P<0.0001). There were significant gender effects on leptin/total fat mass (males, 0.17+/-0.01 ng/ml/kg; females, 0.49+/-0.05 ng/ml/kg; P<0.0001) and relative amounts of fat in SAT and VAT depots (ratio of SAT/VAT; males, 12.3+/-1.5; females, 32.9+/-3.2; P<0.0001). Circulating leptin concentration was significantly correlated with insulin concentration (P=0.001), SAT (P<0.0001) and gender (P=0.033). Circulating concentrations of insulin were significantly correlated with VAT, but not SAT, in males and with SAT, but not VAT, in females. CONCLUSIONS: The sexual dimorphism in the relationship between leptin and adipose tissue mass cannot be explained by differences in the relative amounts of VAT and SAT. Thus, the sexual dimorphism in plasma leptin concentration appears to reflect, at least in part, effects of circulating concentrations of gonadal steroids (especially androgens) and/or primary genetic differences that are independent of amounts of VAT or SAT.

Lack of retroperitoneal lymphadenopathy predicts survival of patients with metastatic renal cell carcinoma.

PURPOSE: Patients with metastatic renal cell carcinoma have a reported 5-year survival of 0% to 20%. The ability to predict which patients would benefit from nephrectomy and interleukin-2 (IL-2) therapy before any treatment is initiated would be useful for maximizing the advantage of therapy and improving the quality of life. MATERIALS AND METHODS: A retrospective analysis of the x-rays and charts of patients treated at the National Institutes of Health Surgery Branch between 1985 and 1996, who presented with metastatic renal cancer beyond the locoregional area and the primary tumor in place, was performed. Preoperative computerized tomography or magnetic resonance imaging, or radiological reports if no scans were available, were used to obtain an estimate of the volume of retroperitoneal lymphadenopathy. Operative notes were used to evaluate whether all lymphadenopathy was resected or disease left in situ, or if any extrarenal resection, including venacavotomy, was performed. Mean survival rate was calculated from the time of nephrectomy to the time of death or last clinical followup. If patients received IL-2 therapy, the response to treatment was recorded. Mean survival and response rate for IL-2 were compared among patients in 3 separate analyses. Patients without preoperatively detected lymphadenopathy were compared with those with at least 1 cm.3 retroperitoneal lymphadenopathy. Also, the patients who had detectable lymphadenopathy were divided into subgroups consisting of all resected, incompletely resected, unresectable and unknown if all disease was resected. Each subgroup was compared with patients without detectable preoperative lymphadenopathy. Patients with less than were compared to those with greater than 50 cm.3 retroperitoneal lymphadenopathy. Patients undergoing extrarenal resection at nephrectomy (complex surgery) due to direct invasion of the tumor into another intra-abdominal organ were compared with those undergoing radical nephrectomy alone, regardless of lymph node status. Statistical analysis was done with the Mantel-Cox test for comparison of survival on Kaplan-Meier curves and with Fisher's exact test for response rates for IL-2. RESULTS: A total of 154 patients with metastatic renal cell carcinoma underwent cytoreductive nephrectomy as preparation for IL-2 based regimens. There were 82 patients with metastatic renal cell carcinoma and no preoperative retroperitoneal lymphadenopathy who survived longer (median 14.7 months) than the 72 with lymphadenopathy (median 8.5, p = 0.0004). Patients with incompletely resected, unresectable or an unknown volume resected had decreased survival compared to those with no retroperitoneal lymphadenopathy. A multivariate analysis of survival was performed evaluating the known prognostic indicators, performance status and tumor burden, as represented by the number of organs involved with metastases, and the new prognostic factor, lymphadenopathy. Lymphadenopathy was more closely associated with survival than performance status, and appeared to be a new prognostic variable. Patients with and without retroperitoneal lymphadenopathy at initial presentation had similar rates for treatment with IL-2 (54% for both groups). Of the 82 patients with no lymphadenopathy 11 (13%) had long-term survival greater than 5 years. Of the 6 complete responses to IL-2, 5 occurred in this group. Only 1 other patient with incompletely resected retroperitoneal lymphadenopathy survived longer than 5 years. No significant difference in survival was seen between patients who did or did not undergo complex surgery. CONCLUSIONS: Patients who presented with metastatic renal cancer and retroperitoneal lymphadenopathy had a shorter survival than those with no detectable retroperitoneal lymphadenopathy. It is warranted to continue to perform complex extrarenal resection during nephrectomy since no significant difference in the response rate for IL-2 or mean survival compared with those of patients undergoing nephrectomy alone is currently detectable.

In vivo determination of body composition of rats using magnetic resonance imaging.

Magnetic resonance imaging (MRI) has potential as an instrument to measure body composition because it can discriminate various soft tissues in vivo. These soft tissues include adipose tissue, muscle, organs, and brain. We report on preliminary studies using a 4.2-tesla MRI for measuring body composition in the mouse and rat. We employed image segmentation methods that include an image correction method, a necessary requirement when the images are taken in the presence of nonuniform radio-frequency (RF) coil response. The software for 3-D data segmentation, quantification, correction, image manipulation, and visualization has been developed as a research tool. This method currently is being validated.

The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells.

Loss of function in the von Hippel-Lindau (VHL) tumor suppressor gene occurs in familial and most sporadic renal cell carcinomas (RCCs). VHL has been linked to the regulation of cell cycle cessation (G(0)) and to control of expression of various mRNAs such as for vascular endothelial growth factor. RCC cells express the Met receptor tyrosine kinase, and Met mediates invasion and branching morphogenesis in many cell types in response to hepatocyte growth factor/scatter factor (HGF/SF). We examined the HGF/SF responsiveness of RCC cells containing endogenous mutated (mut) forms of the VHL protein (VHL-negative RCC) with that of isogenic cells expressing exogenous wild-type (wt) VHL (VHL-positive RCC). We found that VHL-negative 786-0 and UOK-101 RCC cells were highly invasive through growth factor-reduced (GFR) Matrigel-coated filters and exhibited an extensive branching morphogenesis phenotype in response to HGF/SF in the three-dimensional (3D) GFR Matrigel cultures. In contrast, the phenotypes of A498 VHL-negative RCC cells were weaker, and isogenic RCC cells ectopically expressing wt VHL did not respond at all. We found that all VHL-negative RCC cells expressed reduced levels of tissue inhibitor of metalloproteinase 2 (TIMP-2) relative to the wt VHL-positive cells, implicating VHL in the regulation of this molecule. However, consistent with the more invasive phenotype of the 786-0 and UOK-101 VHL-negative RCC cells, the levels of TIMP-1 and TIMP-2 were reduced and levels of the matrix metalloproteinases 2 and 9 were elevated compared to the noninvasive VHL-positive RCC cells. Moreover, recombinant TIMPs completely blocked HGF/SF-mediated branching morphogenesis, while neutralizing antibodies to the TIMPs stimulated HGF/SF-mediated invasion in vitro. Thus, the loss of the VHL tumor suppressor gene is central to changes that control tissue invasiveness, and a more invasive phenotype requires additional genetic changes seen in some but not all RCC lines. These studies also demonstrate a synergy between the loss of VHL function and Met signaling.

Garcinia cambogia (hydroxycitric acid) as a potential antiobesity agent: a randomized controlled trial.

CONTEXT: Hydroxycitric acid, the active ingredient in the herbal compound Garcinia cambogia, competitively inhibits the extramitochondrial enzyme adenosine triphosphate-citrate (pro-3S)-lyase. As a citrate cleavage enzyme that may play an essential role in de novo lipogenesis inhibition, G cambogia is claimed to lower body weight and reduce fat mass in humans. OBJECTIVE: To evaluate the efficacy of G cambogia for body weight and fat mass loss in overweight human subjects. DESIGN: Twelve-week randomized, double-blind, placebo-controlled trial. SETTING: Outpatient weight control research unit. PARTICIPANTS: Overweight men and women subjects (mean body mass index [weight in kilograms divided by the square of height in meters], approximately 32 kg/m2). INTERVENTION: Subjects were randomized to receive either active herbal compound (1500 mg of hydroxycitric acid per day) or placebo, and both groups were prescribed a high-fiber, low-energy diet. The treatment period was 12 weeks. Body weight was evaluated every other week and fat mass was measured at weeks 0 and 12. MAIN OUTCOME MEASURES: Body weight change and fat mass change. RESULTS: A total of 135 subjects were randomized to either active hydroxycitric acid (n = 66) or placebo (n = 69); 42 (64%) in the active hydroxycitric acid group and 42 (61%) in the placebo group completed 12 weeks of treatment (P = .74). Patients in both groups lost a significant amount of weight during the 12-week treatment period (P<.001); however, between-group weight loss differences were not statistically significant (mean [SD], 3.2 [3.3] kg vs 4.1 [3.9] kg; P = .14). There were no significant differences in estimated percentage of body fat mass loss between treatment groups, and the fraction of subject weight loss as fat was not influenced by treatment group. CONCLUSIONS: Garcinia cambogia failed to produce significant weight loss and fat mass loss beyond that observed with placebo.

Positive effects of acarbose in the diabetic rat are not altered by feeding schedule.

We previously demonstrated that chronic dietary treatment with acarbose, an alpha-glucosidase inhibitor, improves glucose homeostasis in the streptozotocin (STZ)-induced diabetic rat. In this study we evaluated the effects of 4 weeks of acarbose treatment on glucose homeostasis in STZ-diabetic rats for both meal-fed (three times daily) and ad libitum feeding conditions. Sprague Dawley male rats (n = 58) were started on a daily meal-feeding paradigm consisting of three 2-h feeding periods: 0700 to 0900 hours, 1300 to 1500 hours, and 1900 to 2100 hours. Following 2 weeks of adaptation, half of the animals were switched to ad libitum feeding. The feeding paradigm itself (meal fed versus ad lib.) affected neither body weight nor daily food intake. Twenty animals from each feeding group then received STZ (60 mg/kg i.v.), whereas control animals received vehicle injections only. Two days later, the diet of 10 STZ-treated animals from each paradigm was supplemented with acarbose (40 mg of BAY G 5421/100-g diet), and the groups were treated for 4 weeks. Untreated diabetic rats had lower body weight than vehicle-injected control rats at all time points after STZ treatment. Acarbose treatment delayed this effect on body weight. STZ treatment induced hyperphagia regardless of feeding paradigm, which was significantly attenuated by acarbose only for the first week of treatment. Untreated diabetic rats had fasting blood glucose values 4 times those of vehicle-injected controls in both the meal-fed and ad libitum-fed conditions. Acarbose significantly lowered fasting blood glucose in the treated STZ groups. Blood glucose was also assessed 0, 90, and 180 min following the start of a meal. The postprandial rise in blood glucose was significantly reduced in acarbose-treated meal-fed diabetic rats, to values not significantly different from those of vehicle-injected control rats. During the fourth week of treatment glycated hemoglobin levels were significantly higher in untreated diabetic groups compared to vehicle-injected control groups. Acarbose treatment significantly reduced this rise, regardless of the feeding paradigm. Collectively, the results demonstrate that acarbose reduces diabetes-induced increases of blood glucose and glycated hemoglobin and that the glycemic effects of acarbose are most apparent during the absorptive period. Feeding paradigm (ad lib. versus meal fed) has little or no influence on acarbose's metabolic effects, indicating that large meals are not required to realize the beneficial effects of the drug. The meal-fed STZ-diabetic rat may be a good model with which to test meal-based diabetes treatments.

A prospective randomized evaluation of the prophylactic use of low-dose dopamine in cancer patients receiving interleukin-2.

The administration of high-dose interleukin-2 (IL-2) causes tumor regression in 17-25% of patients with metastatic melanoma or renal cell carcinoma. Renal dysfunction is a common dose-limiting toxicity of IL-2 administration, limiting 26% of treatment cycles. We have conducted a prospective randomized trial to evaluate whether the prophylactic administration of low-dose dopamine (2 mg/kg/min) can minimize renal toxicity and thus affect the amount of IL-2 administered. Forty-two patients were randomly assigned to receive systemic high-dose IL-2 with standard supportive measures (group A = 21 patients) or with the addition of prophylactic dopamine (group B = 21 patients) at 2 mg/kg/min. For patients in group B, dopamine was instituted 1 h before the initiation of IL-2 administration and was discontinued 6-12 h after the maximum number of doses of IL-2 were given. There was no difference in the amount of IL-2 administered for each course of therapy for groups A and B. Despite differences in urine flow (milliliters per kilogram per day), fluid balance (liters per day), and overall weight gain, prophylactic low-dose dopamine did not significantly alter maximum plasma urea or creatinine levels in group B when compared with the control group (group A). The overall toxicity profile considering all grade 3 and 4 toxicities for patients in groups A and B was comparable. Thus, there is no evidence to support the routine use of prophylactic low-dose dopamine in patients receiving high-dose IL-2.

Differential responsiveness of obese (fa/fa) and lean (Fa/Fa) Zucker rats to cytokine-induced anorexia.

Pathophysiological and pharmacological concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) in the cerebrospinal fluid (CSF) induce anorexia in normal rats. Obesity in humans and rodents is associated with increased TNF-alpha messenger RNA and protein levels in various cell types. This suggests that obese individuals may have differential regulation of cytokine production and dissimilar responsiveness to cytokines. In the present study, we investigated the effects of the intracerebroventricular (ICV) microinfusion of TNF-alpha (50, 100, and 500 ng/rat), IL-1 beta (1.0, 4.0, and 8.0 ng), and TNF-alpha (100 ng) plus IL-1 beta (1.0 ng) on obese (fa/fa) and lean (Fa/Fa) Zucker rats. The results show that: TNF-alpha and IL-1 beta, and the concomitant administration of TNF-alpha and IL-1 beta decreased the short-term (4 hours), nighttime (12 hours), and total daily food intakes in obese and lean rats; IL-1 beta was more potent relative to TNF-alpha; obese rats showed greater responsiveness to IL-1 beta: 8.0 ng IL-1 beta, for example, decreased the 12-hour food intake by 52% in obese and 22% in lean rats. On the other hand, obese and lean rats did not exhibit a significantly different responsiveness to the anorexia induced by 50, 100, or 500 ng TNF-alpha at the 4-hour period; and the concomitant ICV administration of TNF-alpha and IL-1 beta induced anorexia with additive (4-hour period) or synergistic (12-hour and 24-hour periods) effects in obese rats. The effect of TNF-alpha plus IL-1 beta in lean rats was greater than additive for the 12-hour and 24-hour periods. The difference in suppression of total daily food intake by TNF-alpha plus IL-1 beta in obese (-43%) versus lean (-23%) rats was significantly different (p < 0.01). The results show that obese (fa/fa) and lean (Fa/Fa) Zucker rats have differential responsiveness to the ICV microinfusion of two different classes of cytokines.

Treatment with acarbose, an alpha-glucosidase inhibitor, reduces increased albumin excretion in streptozotocin-diabetic rats.

1. We examined the effect of the alpha-glucosidase inhibitor acarbose on urinary albumin excretion (UAE) in streptozotocin diabetic rats. 2. Treatment with acarbose for 8 weeks after induction of diabetes prevented the significant increase in UAE observed in untreated diabetic rats relative to nondiabetic controls. 3. Acarbose significantly reduced integrated glycemia, which correlated with albumin excretion rates, and exerts a salutary effect on diabetic renal dysfunction.

Relationship of adipocyte size to hyperphagia in developing male obese Zucker rats.

In growing male obese Zucker rats, hyperphagia reaches a maximum or "breakpoint" and declines at an earlier age with high fat than with chow-type diets. A serial adipose tissue biopsy technique was used to correlate changes of retroperitoneal adipocyte size and feeding behavior in 5- to 7-wk-old male lean and obese rats fed laboratory chow or a 35% fat diet until 30 wk of age. Although chow-fed groups had significantly greater cumulative intake, fat-fed groups had significantly greater body weight gain, retroperitoneal depot weight, and adipocyte number. Mean adipocyte size increased continuously in chow-fed groups but decreased over weeks 20-30 in fat-fed groups, reflecting increased adipocyte number. In fat-fed obese rats, hyperphagia reached a breakpoint at 11 wk and disappeared by 13 wk. In chow-fed obese rats, hyperphagia reached a breakpoint at 15-16 wk and disappeared by 19 wk. Biopsy samples revealed that adipocyte size of fat-fed obese rats was already close to maximal at 10 wk (1.12 micrograms lipid), while that of chow-fed obese rats only approached maximal at 20 wk (0.81 microgram lipid). At these time points, lipoprotein lipase activity paralleled adipocyte size. These data indicate that the duration of the growing obese rat's hyperphagia coincides with adipocyte filling and suggest the existence of feeding stimulatory and inhibitory signals from adipose tissue.

Beneficial effects of dietary acarbose in the streptozotocin-induced diabetic rat.

Diabetes is characterized by hyperphagia, polydipsia, polyuria, and elevations in blood and urinary glucose. It has also been documented that beta-adrenergic responsiveness is reduced in diabetes. The intestinal glucosidase inhibitor, acarbose (BAY G 5421), decreases postprandial glycemia by delaying carbohydrate absorption. The purpose of this study was to evaluate the effects of chronic acarbose treatment (20 and 40 mg/100 g of diet) on the metabolic and adrenergic parameters altered in streptozotocin (STZ) (50 mg/kg, intravenously [IV] )-induced diabetes. Metabolic parameters were measured daily for 8 weeks. Diabetic rats were hyperphagic, polydipsic, and polyuric within 1 week of STZ treatment. Acarbose treatment did not consistently effect the food intake but did reduce water intake, urinary output, blood glucose, and the urinary loss of glucose associated with STZ-induced diabetes. Adrenergic responses were assessed by monitoring the increase in tail skin temperature (TST) associated with administration of isoproterenol. Diabetic rats were less responsive than controls and acarbose treatment restored responses toward that of the controls. Additionally, 3H-NE release from the tail artery was elevated in the diabetic rat and restored to normal in the acarbose-treated animals. Collectively these data suggest that acarbose treatment is effective in reducing the severity of metabolic and autonomic complications associated with STZ-induced diabetes.

Diet composition determines course of hyperphagia in developing Zucker obese rats.

Previous observations from this laboratory indicate that, during growth, the hyperphagia of the male genetically obese Zucker rat reaches a peak or "breakpoint" and then declines. To examine the effect of dietary macronutrient content on the course of hyperphagia, groups of male lean and obese rats were maintained from 5-28 weeks of age on powdered chow, or isocaloric diets (3.6 kcal/g) containing 72% of calories as corn oil, dextrose, or soy isolate protein (n = 5 lean and obese rats/diet). On chow, hyperphagia was maintained at a level of 7-8 g above lean control intake until a "breakpoint" was reached at 17 weeks, and obese intake declined to lean control level. On the fat diet, hyperphagia was increased to 10 g/day when a breakpoint was reached at 8 weeks. On the dextrose and protein diets, hyperphagia at a level of 3-4 g/day reached breakpoints at weeks 18 and 16, respectively. On all diets, the intakes of obese rats were precisely equal to the intakes of lean control rats by weeks 19-20. These data show that the magnitude and duration of hyperphagia in the developing obese rat are influenced by diet composition. Previously, we have proposed that the obese rat's hyperphagia arises from rapid adipocyte filling. Since high-fat diets facilitate adipocyte enlargement, the early "breakpoint" of hyperphagia seen with the high-fat diet may indicate that this feeding stimulation decreases as the fat cells of the obese rat approach maximal size.

Satiety in the obese Zucker rat: effects of carbohydrate type and acarbose (Bay g 5421).

Despite the obese Zucker rat's hyperphagia on carbohydrate diets such as laboratory chow, this laboratory has found that its satiety response to glucose and other simple sugars is comparable to that of its lean control rat. To further investigate carbohydrate satiety in the Zucker rat, the short-term feeding behavior of obese and lean rats was observed following intragastric infusions (7.2 kcal in 10 ml) of corn starch and the starch hydrolysates Polycose and dextrin. There were no reliable between-genotype differences in the feeding inhibitory effects of Polycose and dextrin. However, in obese rats, the satiety effect of corn starch was delayed and reduced compared to that observed in lean rats (p less than 0.04). To modify the effect of corn starch, rats were administered 0.2 or 0.6 mg/infusion of the carbohydrate digestive inhibitor acarbose (Bay g 5421). Acarbose significantly reduced the satiety effect of corn starch in lean rats (p less than 0.001), and further attenuated satiety in obese rats (p less than 0.02). Since secretion of pancreatic amylase, the enzyme that initiates starch digestion, is decreased in obese rats, this result suggests that alterations of digestive and/or absorptive processes may underlie the obese rat's impaired satiety response to complex carbohydrate.

Tolbutamide affects food ingestion in a manner consistent with its glycemic effects in the rat.

The sulphonylurea tolbutamide possesses the ability to stimulate insulin release, produce hypoglycemia and increase food intake; however, no study has investigated the effects of moderate doses which do not produce frank hypoglycemia. Forty male rats received injections of tolbutamide at 0, 5, 15, 25 or 50 mg/kg body weight. The injections terminated a 2-hr fast and occurred at light offset, insuring a meal. Food intakes were then recorded for two hr following injection. Tolbutamide at 5 and 15 mg doses decreased food intake during the first half-hour or hour, respectively. In parallel experiments, 10 rats were sampled for blood prior to injection of tolbutamide or saline at doses cited above, and again at 10 and 40 min following injection in the absence of food. Plasma was then analyzed for insulin and glucose. Both 5 and 15 mg tolbutamide produced a mild, reliable increase in insulin accompanied by a decrease of 5 to 15 mg/dl in plasma glucose. On the other hand, the 50 mg dose produced a marked increase in insulin and a decrease of approximately 25% in plasma glucose. Thus, the present studies suggest that when endogenous insulin levels are modestly raised by tolbutamide, such that only moderate reductions of circulating glucose were observed, decreases in food intake occur.