Biomedical subjects

M I Friedman

Publications and source records attributed to M I Friedman.

At least 37 records · Page 2Linked to original sources

PubMed1997

An energy sensor for control of energy intake.

Control of energy intake, either in response to changes in the energy content of food or in energy expenditures and storage, is based on the detection of a feedback signal generated in the processing of metabolic fuels for energy. Evidence from studies of the fructose analogue, 2,5-AM, indicates a sensor in liver responds to changes in intracellular ATP or some closely associated event and communicates this information to the brain via vagal afferent neurons. Such a mechanism could serve as the energy sensor which controls energy intake.

Animals↗

PubMed1997

Satiety from fat? Adverse effects of intestinal infusion of sodium oleate.

To determine whether damage to the intestinal mucosa by oleic acid causes the suppression of food intake observed in response to intraintestinal infusion of the fatty acid, we measured lactate dehydrogenase (LDH) activity, a marker for cell damage, in the intestinal lumen after intestinal infusion of fatty acid under conditions similar to those employed in studies of eating behavior. Infusions of 25 or 51 mM sodium oleate (neutralized oleic acid) markedly and rapidly increased LDH activity, whereas infusions of saline had little or no effect. Infusion of octanoate, which has been reported to be ineffective in reducing eating behavior, did not increase intestinal LDH activity relative to saline infusion. Similarly, infusion of ethyl oleate or free (nonneutralized) oleic acid neither increased luminal LDH activity nor suppressed food intake. Infusion of sodium oleate also produced a strong conditioned aversion to sucrose. The results strongly suggest that the suppression of food intake induced by intraintestinal infusion of sodium oleate is due to the injurious effects of this unphysiological form of the fatty acid.

Animals↗

PubMed1997

Image enhancement of severely hypoperfused myocardia for computation of tomographic ejection fraction.

UNLABELLED: Ejection fractions computed from 99mTc-sestamibi myocardial perfusion gated tomograms have demonstrated a high degree of accuracy and reproducibility. Although automated algorithms appear to provide reasonable endocardial outlines for patients over a broad spectrum of cardiac diseases, in cases of severe hypoperfusion, it is necessary to manually adjust contrast and brightness to judge whether borders are correct or must be altered. METHODS: Midventricular horizontal and vertical long axis gated tomograms were generated for 116 studies chosen on the basis of extensive, severe myocardial perfusion defects. Automated software transformed cinematic tomograms into images demonstrating uniform appearance of the myocardium throughout the cardiac cycle. Transformed images were introduced to edge detection algorithms for subsequent calculation of ventricular volumes and ejection fractions. RESULTS: Linear regression analysis demonstrated excellent intraobserver reproducibility for ejection fractions (r = 0.95) and volumes (r = 0.98). There was also good agreement of ejection fractions (r = 0.86) and volumes (r = 0.94) with values derived from an expert's manual drawings. In a subgroup of 22 patients, automated ejection fractions from transformed images demonstrated better agreement with independent first-pass values (r = 0.90) than did manual measurements derived from original data (r = 0.85). CONCLUSION: Image enhancement algorithms succeeded in providing accurate, reproducible gated SPECT ejection fractions in the most difficult class of patients exhibiting severe hypoperfusion.

Aged↗

PubMed1996

Gastric emptying of ingested fat emulsion in rats: implications for studies of fat-induced satiety.

Evidence that ingested fat acts in the intestine to produce satiety stems from studies showing that intraintestinal infusion of fat emulsion inhibits eating behavior of rats. In this study, we determined the appropriateness of infusion parameters used in these behavioral studies by measuring gastric emptying rates of both the aqueous and lipid components of Intralipid ingested normally by rats. Stomach contents were collected at different times 0-40 min after rats ingested Intralipid containing [14C]polyethylene glycol (PEG) and phenol red (PR) and were assayed for PEG, PR, and fat. The proportion of ingested fat remaining in the stomach was significantly greater than the proportion of ingested PEG or PR at all time points examined. Despite initial gastric emptying of fat during ingestion, consumption of Intralipid (0.5 or 1.1 kcal/ml) did not suppress subsequent solid food intake. The results indicate that 1) ingested fat emulsion rapidly partitions in the rat stomach into an aqueous phase, which empties rapidly, and a lipid phase, which empties slowly, and 2) normal ingestion of Intralipid is not immediately satiating. These observations raise questions about the physiological significance of the rapid and marked suppression of feeding behavior produced by intraintestinal infusion of Intralipid.

Animals↗

PubMed1996

Does ingested fat produce satiety?

Administration of fat directly into the gastrointestinal tract of rats produces a rapid and often substantial reduction of feeding behavior. This contrasts with the normal consumption of a fat meal, which produces little change in subsequent food intake. To determine whether procedural differences account for this discrepancy, we examined the satiating effect of ingested fat on food intake of rats maintained under feeding conditions similar to those employed in studies involving gastrointestinal delivery of fat (i.e., food deprivation, liquid diet). Ingestion of approximately 1.5 ml corn oil had no effect on subsequent liquid diet intake until 90 min after oil ingestion. When rats ingested oil 4 h before access to the liquid diet, to allow time for additional gastrointestinal clearance, liquid diet intake was reduced by 13% in the first 30 min of access. These findings indicate that ingested fat decreases short-term intake slightly, but only if time is allowed for postabsorptive delivery. The results question the physiological significance of the marked suppression of food intake observed in response to administration of fat directly into the gastrointestinal tract.

Animals↗

PubMed1996

A comparison of the effects of food deprivation and 2,5-anhydro-D-mannitol on metabolism and ingestion.

Using respiratory quotient as an index of metabolic state, we compared the effects of administrations of the fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) at a dose of 300 mg/kg with the effect of 10 h of food deprivation. We measured behavioral and physiological responses of the animals receiving the two treatments, including food intake, energy expenditure, rates of carbohydrate and fatty acid utilization, and plasma levels of glucose, insulin, corticosterone, epinephrine, and norepinephrine. A vehicle-treated control group was also included. Fasting produced a greater food intake than 2,5-AM administration. Although plasma glucose, insulin, and norepinephrine levels were similar between the two treatments, plasma corticosterone and epinephrine levels were significantly elevated in animals receiving 2,5-AM. We conclude that although 2,5-AM can produce a metabolic state similar to fasting, as measured by an index of whole body metabolic state (respiratory quotient), there remain factors that influence food intake that are not similar in the two conditions.

Animals↗

PubMed1996

Fatty acid oxidation modulates the eating response to the fructose analogue 2,5-anhydro-D-mannitol.

The fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) stimulates feeding behavior in rats apparently through its effects on hepatic energy metabolism, where it reduces glucose utilization, traps phosphate, and decreases ATP. The extent to which the magnitude and duration of the eating response are dependent on the ability of the liver to switch to fat oxidation for energy production was investigated by manipulating substrate availability through dietary and pharmacological means. Rats adapted to a high-fat, low-carbohydrate diet preferentially use fat fuels for hepatic energy production and were insensitive to the effects of 2,5-AM on food intake. The lack of an eating response occurred despite similar changes in plasma fuels and liver glycogen compared with rats fed a low-fat, high-carbohydrate diet. In contrast, inhibiting fatty acid oxidation with methyl palmoxirate, which blocks transport of long-chain fatty acids to the mitochondria, potentiated the ability of 2,5-AM to stimulate feeding without altering its effects on plasma and liver fuels. These data demonstrate that the eating response to 2,5-AM is modulated by the availability of fat fuels and implicate a mechanism for initiation of feeding that is not dependent on inhibition of carbohydrate metabolism per se but rather integrates information about the use of both types of fuels.

Animals↗

PubMed1995

Control of energy intake by energy metabolism.

Eating behavior is controlled by signals that are generated in the postabsorptive metabolism of energy-yielding substrates. Recent work indicates that an event common to the metabolism of glucose and fat provides such a signal. Evidence suggests that eating behavior is triggered by a signal that is tied to hepatic ATP concentrations and is carried from the liver to brain via afferents in the vagus nerve. This metabolic control of eating behavior may link mechanisms of energy storage and expenditure to energy intake. Changes in energy intake associated with alterations in energy expenditure can be viewed as a response to a shift in the partitioning of fuels, which affects the oxidative metabolic pathways that generate the signal controlling eating behavior.

Animals↗

PubMed1995

Whole body energy expenditure and fuel oxidation after 2,5-anhydro-D-mannitol administration.

The fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) increases food intake in nondeprived rats. Several lines of evidence indicate that vagal signals arising from the liver are critical for this effect. In addition, 2,5-AM decreases plasma glucose and increases lipolysis, resulting in an increase in plasma free fatty acids and ketone bodies. In these respects 2,5-AM produces a state analogous to that observed after food deprivation. Using an indirect calorimeter, we determined that 2,5-AM (300 mg/kg ip) causes a potent and long-lasting decrease in respiratory quotient, indicating a decrease in the fraction of total energy derived from carbohydrate oxidation and an increase in the fraction derived from fatty acid oxidation. These metabolic variables were altered without affecting total metabolic rate. This dose of analogue also stimulated significantly greater food intake than injections of vehicle. These results support the continued use of 2,5-AM as a tool to probe the metabolic controls of food intake.

Analysis of Variance↗

PubMed1995

Parabrachial nucleus lesions impair feeding response elicited by 2,5-anhydro-D-mannitol.

Systemic injection of the fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) elicits a feeding response and induces c-fos activity in the parabrachial nuclei (PBN). We used bilateral ibotenic acid lesions of PBN to determine whether the activation inferred from c-fos activity was causally related to the feeding response. The relationship between the PBN lesion and feeding behavior was also examined with the glucose analogue 2-deoxy-D-glucose (2-DG). The PBN lesions interfered with the feeding response to 2,5-AM but spared the feeding response to 2-DG. Rats were also tested in a conditioned taste-aversion paradigm. Differences were observed in the relationship between lesion extent and behavioral deficit for feeding responses to 2,5-AM and taste-guided intake after taste-aversion conditioning. These data provide the first demonstration that central lesions can disrupt feeding responses to peripherally acting 2,5-AM. The results suggest that the neural substrate for this response differs from that mediating taste-aversion conditioning and from that involved in the feeding response to 2-DG.

Animals↗

PubMed1995

Regulation of food intake by metabolic fuels in white-crowned sparrows.

Migratory birds rely on increased fat storage and fatty acid utilization to meet seasonal changes of energy expenditure and as a result increase food intake and fat stores before migration. To determine whether their feeding behavior is sensitive to carbohydrate and/or fatty acid utilization, white-crowned sparrows maintained on short daylength (9L15D) were injected intraperitoneally with 2-deoxy-D-glucose (2-DG) or 2,5-anhydro-D-mannitol (2,5-AM). Low doses of 2-DG (25 or 50 mg/kg) had no effect on food intake, and higher doses (100 or 300 mg/kg) significantly suppressed feeding after 1 and 2 h. No dose of 2-DG increased meal size. Similarly, low doses of 2,5-AM (25, 50, or 100 mg/kg) had no effect on food intake, and higher doses (300 and 600 mg/kg) significantly suppressed intake. These data suggest that decreased carbohydrate metabolism does not elicit feeding in this species. Importantly, these drugs, as well as insulin and glucagon, were demonstrated to increase plasma fatty acids as well as to decrease feeding. Injections of tributyrin (100, 300, 600, or 2,000 mg/kg i.p.) or glycerol (300, 450, and 600 mg/kg) also significantly suppressed 60-min and 120-min food intake dose dependently in these birds, and equimolar glucose (1,200 mg/kg) had no effect. We conclude that feeding by the white-crowned sparrow is unresponsive to manipulations of carbohydrate metabolism and is decreased after manipulations that increase plasma lipids.

Animals↗

PubMed1994

Induction of Fos-like immunoreactivity (Fos-li) and stimulation of feeding by 2,5-anhydro-D-mannitol (2,5-AM) require the vagus nerve.

The antimetabolic fructose analogue, 2,5-anhydro-D-mannitol (2,5-AM), stimulates feeding. Selective hepatic branch vagotomy has been shown to block feeding induced by low 2,5-AM doses. However, hepatic vagal fibers are not the sole mediators of 2,5-AM-induced feeding, since hepatic branch vagotomy does not impair feeding induced by higher doses of 2,5-AM. To further evaluate the role of the vagus in the response to 2,5-AM, we examined the effect of total subdiaphragmatic vagotomy on feeding induced by a high 2,5-AM dose (500 mg/kg). In addition, we assessed the ability of 2,5-AM (300 and 500 mg/kg) to induce Fos-like immunoreactivity (Fos-li) in the brain in sham-operated (SHAM), hepatic branch vagotomized (HBV) and total subdiaphragmatic vagotomized (TSDV) rats. Both doses of 2,5-AM, but not control solutions, induced Fos-li in the area postrema (AP), nucleus of the solitary tract (NTS) and lateral parabrachial nucleus (1PBN). Very weak immunoreactivity was present in the central nucleus of the amygdala and none was observed in the locus coeruleus or paraventricular nucleus of the hypothalamus. The effect of the lower 2,5-AM dose on Fos-li was blocked by HBV. The high dose effect was blocked by TSDV but not by HBV. Feeding induced by the high dose of 2,5-AM was also blocked by TSDV. Results are consistent with the hypothesis that stimulation of feeding by 2,5-AM is dependent on the vagus nerve. Hepatic branch fibers may have the lowest threshold for activation, but fibers in other vagal branches independently mediate induction of c-fos and stimulate food intake at higher doses of the analogue.

Animals↗

PubMed1994

Limonene in expired lung air of patients with liver disease.

As part of an effort to examine the relationship between chemosensory disturbance and oral chemistry, we analyzed expired lung air samples from a series of 24 patients with liver disease and 24 healthy controls using gas chromatography-mass spectrometry. Compared to samples from controls, lung air from patients with liver disease contained unusually high levels of limonene, a monoterpene that is a major component of the essential oil of citrus fruits (0.1 vs 7.0 micrograms/20 liters for controls and patients). Only half the patients showed high levels of limonene. Patients with noncholestatic liver disease were significantly more likely to have elevated lung air limonene levels than those with cholestatic liver disease (0.2 vs 13.8 micrograms/20 liters). Responses to food frequency and dietary behavior questionnaires indicated a pattern of diet selection and food preferences that were consistent with a dietary origin for the limonene in these patients.

Air↗

PubMed1994

Food intake in diabetic rats: relationship to metabolic effects of insulin treatment.

Hyperphagic streptozotocin-diabetic rats were given week-long treatment with 0 (vehicle), 3, or 6 U/rat/day of regular insulin via a SC osmotic pump. Insulin reduced urinary glucose excretion and plasma glucose and increased body weight in a dose-related manner starting on the first day of treatment. Insulin treatment also increased carcass weight, carcass fat, and liver glycogen within 3 days. Food intake did not decrease until the fifth day of insulin treatment, and this change was unrelated to the amount of insulin administered. These results show that the effects of insulin on food intake and metabolism of diabetic rats can be dissociated with respect to both time course and dose of insulin. The findings indicate that hypoinsulinemia, glycosuria, body weight loss, and depletion of body fat and liver glycogen are symptoms of diabetes, not causes of diabetic hyperphagia.

Animals↗

PubMed1994

Altered hepatic metabolic response to carbohydrate loads in rats with hepatic branch vagotomy or cholinergic blockade.

Hepatic pyruvate, lactate and glycogen concentrations were measured 40 min after gavage of 5 ml 35% fructose or glucose to rats with sham surgery or section of the hepatic branch of the vagus nerve. Other animals were treated with saline or the peripheral anticholinergic drug, atropine methyl nitrate, prior to gavage of fructose. The increase in pyruvate concentration produced by the carbohydrate loads was attenuated by both hepatic vagotomy and cholinergic blockade. The increase in lactate concentration after a fructose load was attenuated by hepatic branch vagotomy but not atropine injection. The increase in glycogen deposition after a fructose load was attenuated by atropine injection but not hepatic branch vagotomy. These results suggest that the hepatic metabolic response to fructose and glucose loads in rats depends on a functional parasympathetic nervous system.

Animals↗

PubMed1994

Relationship between liver biochemical tests and dietary intake in patients with liver disease.

Relationships between liver biochemical test values and reported frequency of consumption of various foods were examined using a principal-component analysis of data from 42 patients with chronic liver disease. The statistical procedure identified relationships among biochemical and dietary variables. One relationship included the variables albumin, bilirubin, and frequency of intake of fruits and vegetables, starch, and meats. A relationship was also found between serum alkaline phosphatase (ALP) levels and fat/oil intake. Data from patients with primary biliary cirrhosis (PBC) and noncholestatic liver disease were compared using a correlational analysis. In patients with PBC, serum ALP levels were positively correlated with frequency of intake of fat/oil (r = 0.59, p < 0.01) and meats (r = 0.46, p < 0.05), whereas serum bilirubin (Bili) and aspartate aminotransferase (AST) levels were significantly correlated with frequency of intake of dairy products (rs = 0.48 and 0.45, ps < 0.05 for Bili and AST, respectively), meats (rs = 0.59 and 0.65, ps < 0.01), and fat/oil (r = 0.54, p < 0.02 and r = 0.48, p < 0.05). In patients with noncholestatic liver disease, Bili levels were correlated with frequency of intake of fat/oil (r = 0.58, p < 0.01), and fruits and vegetables (r = 0.68, p < 0.01). These results suggest that the degree of elevation of some liver biochemical tests in patients with liver disease may be affected by dietary intake.

Alkaline Phosphatase↗

PubMed1994

Hepatic phosphate trapping, decreased ATP, and increased feeding after 2,5-anhydro-D-mannitol.

The mechanism by which the fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) elicits feeding behavior was investigated by studying its metabolism and biochemical effects in liver. Thin-layer chromatography of liver extracts from rats given 2,5-AM containing 14C-labeled 2,5-AM showed that the analogue is phosphorylated in vivo with a time course that parallels the eating response. In vivo 31P nuclear magnetic resonance spectroscopy of rat liver during intravenous infusion of 2,5-AM and high-resolution nuclear magnetic resonance analyses of liver extracts showed that 2,5-AM is rapidly phosphorylated in liver, trapping hepatic phosphate and decreasing ATP, inorganic phosphate, and phosphate diesters. These changes occurred in a time frame in which the feeding response is elicited in conscious animals given the same dose of 2,5-AM by the same route. During an interval in which 2,5-AM increased eating, it also increased urinary uric acid excretion, implicating enhanced adenosine degradation in the reduction in hepatic ATP. These results provide the first direct evidence that changes in a high-energy phosphate-carrying compound in liver may provide a signal to initiate eating behavior.

Adenosine Triphosphate↗

PubMed1994

Phosphate loading prevents the decrease in ATP and increase in food intake produced by 2,5-anhydro-D-mannitol.

The fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) triggers feeding in rats apparently by its action in the liver. In vivo phosphorylation of this analogue decreases hepatic inorganic phosphate and ATP by trapping of phosphate in the mono- and diphosphorylated forms of 2,5-AM. To determine whether hepatic phosphate depletion and decreased ATP are involved in the eating response to 2,5-AM, rats were treated with excess sodium phosphate before injection of 2,5-AM. Phosphate loading prevented both the increase in food intake and the decrease in liver ATP, without affecting the changes seen in plasma fuels produced by 2,5-AM treatment. Phosphate loading did not influence water intake or eating elicited by insulin or 2-deoxy-D-glucose, indicating that the effect on 2,5-AM-induced eating was behaviorally specific and not due to malaise. These data suggest that 2,5-AM elicits eating by trapping phosphate and reducing ATP in liver.

Adenosine Triphosphate↗