Influence of alcohol and sucrose consumption on energy balance and brown fat activity in the rat

Voluntary intake of solutions of alcohol (7%) and sucrose (10%) represented 20% and 25% of total metabolizable energy intake, respectively, in young male rats maintained on a stock diet, but total energy intake was similar to that of controls drinking water. Body weight and energy gains were similar for control and sucrose-treated rats but were significantly reduced in the group drinking alcohol, and energy expenditure, corrected for body size (kJ/kg0.75/day), was elevated in rats drinking alcohol (17% above control) or sucrose (18%). Gross and net energetic efficiencies were markedly depressed by consumption of alcohol but not by consumption of sucrose. Resting oxygen consumption, before and after injection of norepinephrine (25 micrograms/100 g body weight) was similar for all groups. Brown adipose tissue (BAT) mass and mitochondrial protein did not differ between groups, but the activity of the mitochondrial proton conductance pathway, assessed from the binding of 3H-guanosine diphosphate, was significantly elevated by alcohol and sucrose consumption. Thus, the increased energy expenditure associated with alcohol and sucrose ingestion may involve BAT thermogenesis, but this alone cannot explain the larger effects of alcohol on metabolic efficiency.     

Energy balance and brown fat activity in rats fed cafeteria diets or high-fat, semisynthetic diets at several levels of intake

The object of the study was to determine the relative effects of hyperphagia and diet composition on energy balance and thermogenic activity in rats fed highly palatable cafeteria diets. Three types of diet were used: a pelleted stock diet, a cafeteria diet composed of a variety of human food items, and semisynthetic diets with nutrient compositions similar to the stock and cafeteria diets. Feeding rats a high-fat semisynthetic diet (similar to the cafeteria diet) at a energy intake equivalent to that of stock-fed controls (approximately 2.5 times maintenance) resulted in greater body energy gains and energetic efficiencies. These effects were probably due to the reduced energy costs of fat synthesis associated with high-fat diets. No effect of dietary composition on body energy gain was seen in animals fed below 2.5 times maintenance. Animals fed four cafeteria food items each day, or the high-fat semisynthetic diet, at 2.5 times maintenance showed significantly greater thermogenic responses to norepinephrine, increased brown adipose tissue (BAT) mass, and greater BAT mitochondrial GDP binding than controls on the same intake. Injection of propranolol reduced oxygen consumption in all groups, but the effect was greater in animals on higher intakes and was highest in the cafeteria groups. Thus, increasing fat intake, either by presenting cafeteria food items or by feeding a high-fat semisynthetic diet at the same level of intake as controls, stimulates the sympathetic nervous system and BAT activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

A role for insulin in the diet-induced thermogenesis of cafeteria-fed rats

Rats fed a varied and palatable “cafeteria” diet exhibited hyperphagia, increases in resting metabolic rate (VO₂) and the thermogenic response to noradrenaline as well as hypertrophy of brown adipose tissue (BAT). In streptozotocin-diabetic rats, cafeteria feeding failed to produce increases in VO₂ or the response to noradrenaline, although BAT mass was greater than in their respective stockfed controls. Replacement doses of insulin (protamine-zinc-insulin, PZI) at two levels (2 and 4 units/rat every alternate day) failed to restore the thermogenic response of diabetic rats to the cafeteria diet. Acute replacement (8 units PZI) 12hr before the measurements resulted in resting and noradrenaline-stimulated values for VO₂ that were similar to those of non-diabetic cafeteria rats. These findings suggest an insulin requirement for diet-induced thermogenesis and the failure of diabetic rats to maintain body temperature when exposed to cold (5°C) suggests a further insulin requirement for cold-induced thermogenesis. In non-diabetic cafeteria rats, plasma insulin levels were significantly lower than those of stock fed controls in spite of a high carbohydrate intake and normal blood glucose.     

Involvement of insulin in the acute thermogenic responses to food and nonmetabolizable substances

Gastric intubation with 40 kJ of a carbohydrate slurry (4 mL) produced increases in resting oxygen consumption (VO2) of 15% to 22% in control, cold-adapted, and hyperthyroid rats, but the absolute rise in metabolic rate after food was greater in the latter group. Tube-feeding methyl cellulose (4 mL, 7% wt/vol) evoked similar increases in VO2 to carbohydrate (15% to 23%), but all of these responses were inhibited by beta-adrenergic blockade with propranolol. In cold-adapted animals, fat (40 kJ, 1.2 mL) produced a greater thermic effect than carbohydrate or methyl cellulose, and water (4 mL) also induced a small (8%), significant increase in VO2. Treatment with diazoxide shortly before the meal, to inhibit insulin release, almost completely inhibited the thermic responses to carbohydrate and methyl cellulose in all groups, but did not alter the effects of fat or water. Ingestion of a nonmetabolizable substance (methyl cellulose), would appear to stimulate metabolic rate to a similar extent to carbohydrate, possibly by causing gastric distention. Thermic effects of both these substances appear to involve insulin release and activation of the sympathetic nervous system. The thermic response to fat can also be inhibited by beta-adrenergic blockade, but apparently does not involve insulin release.     

Mechanisms of thermogenesis induced by low protein diets

Weanling (22-day-old) rats fed a low protein (8% casein) diet consumed the same amount of energy as controls (22% casein diet), but intake corrected for body size (kJ/kg0.75) was increased in the former group. Weight gain and the efficiency of gain (g gain/MJ) were markedly reduced in low protein fed rats. Resting oxygen consumption (VO2) was elevated by 15% in the low protein group but this difference was completely abolished by beta-adrenergic blockade with propranolol. Interscapular brown adipose tissue (BAT) mass, protein content, mitochondrial yield and GDP binding were increased in low protein fed rats but mitochondrial alpha-glycophosphate shuttle activity of BAT was unaltered, although shuttle activity was elevated in liver mitochondria. Plasma triiodothyronine levels were increased by 64% in the low protein group, whereas insulin levels were markedly reduced in spite of normal blood glucose levels. Resting VO2 and BAT mass were also increased in older (55-day-old) rats fed the low protein diet, but the changes were smaller than in weanling rats. These data suggest that the decreased metabolic efficiency seen in rats fed protein deficient diets involves sympathetic activation of BAT, and is therefore similar to the thermogenic responses seen in cold adapted and cafeteria-fed animals.     

Impact of bicycle provision on the health of refugees in London: a qualitative study

Background

Refugees are a growing population in London and experience barriers to regular meaningful exercise. Research shows that cycling as a form of exercise is often overlooked by minority ethnic groups. In London, UK, The Bike Project is a charity that reconditions bicycles, donates them to refugees, and offers cycle proficiency training. This study aimed to explore the impact of being provided with a free bicycle and involvement with the charity on the wellbeing of refugees in London.

The influence of glucose on serum galactose levels in man

To investigate the effect of simultaneous glucose and galactose administration on serum galactose levels in man, volunteers were given a standard galactose meal of 0.5 g galactose/kg BW alone and with various body weight related glucose loads and with fructose; lactose was also given to a group of volunteers. Two groups of subjects received the standard galactose meal alone and with a simultaneous intravenous infusion of glucose or insulin. There was a marked individual variation in the serum galactose response to the standard galactose meal, the maximum galactosemia ranged from 0.23 to 4.56 mmole/L. Peroral glucose suppressed the serum galactose response to galactose producing significant reductions in the mean area under the serum galactose response curves. At a glucose intake of 0.15 g/kg by-32 +/- 14.3%, 0.50 g/kg BW -69 +/- 5.93% and at 0.75 g/kg BW -75 +/- 4.93%. Ingestion of glucose with galactose did not increase galactose loss in the urine. Lactose produced similar serum galactose, glucose and insulin responses to those seen after administration of equal quantities of galactose and glucose as monosaccharides. Fructose did not affect serum galactose levels when given with the standard galactose meal. Intravenous glucose produced a significant reduction of 56 +/- 14.1% in the mean area under the galactose response curve [p less than 0.01], whereas intravenous insulin did not affect the serum galactose response to peroral galactose.     

Oxidation and ketogenesis in hepatocytes of lean and obese Zucker rats

Ketone body production and oxidation of ¹⁴C fatty acids to CO₂ were measured in hepatocytes isolated from lean and obese Zucker rats. The oxidation of [1-¹⁴C]octanoate, [1-¹⁴C]palmitate and [1-¹⁴C]palmitoyl carnitine to ¹⁴CO₂ was 50%–70% less in obese than in lean rats. Although ketone body production in hepatocytes from both lean and obese rats was increased by fasting, there was a significantly lower rate of ketone body production in hepatocytes from obese rats. Ketone body production was reduced to a comparable extent by increasing the glucose concentration in the incubation media of hepatocytes from both lean and obese rats. Glucagon and carnitine increased ketogenesis and the effects were additive and similar in lean and obese rats. These data suggest that β-oxidation and ketogenesis are suppressed in the obese Zucker rat, and further that ketone bodies can be modulated similarly in hepatocytes from lean and obese rats by nutritional and hormonal intervention. It is postulated that the decreased β-oxidation and ketone body production may play a role in the development or maintenance of obesity in the Zucker rat.     

Metabolic consequences of fasting in old lean and obese Zucker rats

The effects of fasting on lipid and carbohydrate metabolism and plasma insulin and glucagon levels were compared in lean and obese Zucker rats. Sixteen-month-old female and male rats were fasted for periods of 2, 4, 6 and 12 days. Fasting produced significant decreases in hepatic rates of lipid, cholesterol, and glycogen synthesis, as well as circulating levels of triglycerides, cholesterol, phospholipids, and insulin. Significant increases in hepatic lipid levels and serum free fatty acids were noted. When compared to lean rats, obese rats had elevated rates of hepatic lipid and glycogen synthesis, hepatic lipid and glycogen stores, serum triglycerides, cholesterol, phospholipids, and plasma insulin. Lean rats had higher plasma glucagon levels. Sex differences in several parameters were observed. Females demonstrated higher levels of lipid and cholesterol synthesis and serum free fatty acids, whereas serum cholesterol levels and hepatic glycogen stores were higher in males. Following a 12-day fast, carcass fat and protein content were decreased in both lean and obese rats, but the obese animals maintained an obese body composition. It is concluded that fasting results in qualitatively similar metabolic and hormonal changes in both lean and obese rats, but that abnormalities in carbohydrate and lipid metabolism persist in obese rats even after a 12-day fast.     

Beta blockade and diabetes mellitus: effect of oxprenolol and metoprolol on the metabolic, cardiovascular, and hormonal response to insulin-induced hypoglycemia in normal subjects

In a double-blind randomized study, the effect of the acute administration of a single oral dose of oxprenolol, a nonselective beta-blocker, and of metoprolol, a beta 1 selective blocker, on insulin-induced hypoglycemia was tested in seven normal subjects. Neither of the drugs potentiated the hypoglycemic effect of insulin. The recovery from hypoglycemia was delayed by both blocking agents only in the late phases of the experimental observation. This effect could not be accounted for by suppression of release of the counterregulatory hormones glucagon or cortisol, but may be mediated by the inhibition of NEFA and gluconeogenic-substrate release in response to hypoglycemia. Both drugs blocked the hypoglycemia-induced tachycardia. Only oxprenolol raised diastolic blood pressure during hypoglycemia. Symptoms of hypoglycemia were not masked by either blocking agent, and sweating was enhanced and prolonged by both drugs. Thus, no clear-cut differences in the glycemic response to insulin-induced hypoglycemia were found between metoprolol and oxprenolol, but the drugs differed in their influence upon the blood pressure response to insulin-induced hypoglycemia.     

The effect of glycerol and other intermediates on the incorporation of 14C-fructose and 14C-glucose to hepatic triglyceride

Mature male rats were given, orally, ¹⁴C-fructose either alone or in conjunction with dihydroxyacetone, glyceraldehyde, or glycerol. Glycerol was also administered with ¹⁴C-glucose in a dose equimolar with fructose. After 2 hr the rats were killed and the liver triglyceride fraction was separated. Estimations of the degree of incorporation of ¹⁴C from the radioactive labeled carbohydrate into the glycerol and fatty acid moieties were carried out. Dihydroxyacetone and glyceraldehyde reduced the incorporation of ¹⁴C-fructose into hepatic triglyceride to approximately equal extents, suggesting that both trioses contribute equally to α-glycerophosphate formation. Glycerol, however, brought about a profound increase in the amount of fructose converted to triglyceride. This effect of glycerol was not apparent to any measurable extent on glucose incorporation into triglyceride and none of the intermediates affected the proportional distribution of radioactive counts between the fatty acid and glycerol moieties of the triglyceride after ¹⁴C-fructose administration.     

Serum cholesterol, lecithin-cholesterol acyltransferase, and hepatic hydroxymethylglutaryl coenzyme A reductase activities of lean and obese Zucker rats

Serum cholesterol concentrations, lecithin-cholesterol acyltransferase (LCAT), and hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activities of lean and obese Zucker rats were compared. The excess serum cholesterol of the female obese rat is found to be mainly free cholesterol associated with very low-density lipoproteins, whereas that of the male obese rat is carried as cholesterol esters associated with high-density lipoproteins. The high level of serum free cholesterol in the female obese rat is not due to a deficiency in lecithin-cholesterol acyltransferase activity. This enzyme activity is found to be elevated in the male obese rat. Hepatic HMG-CoA reductase activity declines as rats mature; this observation is most apparent in obese male rats. Lean rats exhibit the normal diurnal rhythm, but mature obese rats show little diurnal variation in HMG-CoA reductase activity. Obese female rats maintain high reductase activities, but the activities of obese male rats remain low at all times. Starvation suppresses liver HMG-CoA reductase and serum cholesterol in both lean and obese female rats. Thus, an increase in hepatic cholesterol synthesis may contribute to hypercholesterolemia in the obese female Zucker rat. On the other hand, factors such as nonhepatic synthesis or a decreased cholesterol catabolism may play more important roles in maintaining high serum cholesterol in the obese male Zucker rat.     

Effect of dietary composition on fasting-induced changes in serum thyroid hormones and thyrotropin.

To assess the effect of starvation and refeeding on serum thyroid hormones and thyrotropin (TSH) concentrations, 45 obese subjects were studied after 4 days of fasting and after refeeding with diets of varying composition. All subjects showed an increase in both serum total and free thyroxine (T₄), and a decrease in serum total and free triiodothyronine (T₃) following fasting. These changes were more striking in men then in women. The serum T₃ declined during fasting even when the subjects were given oral L-T₄, but not when given oral L-T₃. After fasting, the serum reverse T₃ (rT₃) rose, the serum TSH declined, and the TSH response to thyrotropin-releasing hormone (TRH) was blunted. Refeeding with either a mixed diet (n = 22) or a carbohydrate diet (n = 8) caused the fasting-induced changes in serum T₃, T₄, rT₃, and TSH to return to control values. In contrast, refeeding with protein (n = 6) did not cause an increase in serum T₃ or in serum TSH of fasted subjects, while it did cause a decline in serum rT₃ toward basal value.The present data suggest that: (1) dietary carbohydrate is an important factor in reversing the fall in serum T₃ caused by fasting; (2) production of rT₃ is not as dependent on carbohydrate as that of T₃; (3) men show more significant changes in serum thyroid hormone concentrations during fasting than women do, and (4) absorption of T₃ is not altered during fasting.     

Beta blockade and diabetes mellitus: effect of oxprenolol and metoprolol on the metabolic, cardiovascular, and hormonal response to insulin-induced hypoglycemia in insulin-dependent diabetics

The effect of the administration of a single oral dose of placebo, oxprenolol and metoprolol on insulin-induced hypoglycemia was investigated in seven insulin-dependent diabetics in a double-blind randomized study. Neither of the beta-blocking agents accelerated the plasma glucose lowering effect of insulin. Plasma glucose recovery from hypoglycemia was grossly impaired in diabetics whether blocked or not, and all investigations had to be terminated by i.v. glucose injection after 1 hr of sustained hypoglycemia. During the period of observation, no further delaying effect by either beta-blocker was observed. The lack of plasma glucose recovery seems to be at least in part related to a retarded and reduced glucagon response to hypoglycemia. Both drugs blocked the hypoglycemia-induced pulse rate increase, but neither caused bradycardia. A significant increase in diastolic pressure was recorded with oxprenolol, whereas a drop in systolic pressure was noted with metoprolol. Oxprenolol suppressed the NEFA rise after insulin-infusion termination to a greater extent than did metoprolol. Hypoglycemic symptoms were not affected by beta-blockade. The results suggest that neither drug further worsens the already grossly impaired plasma glucose recovery, but that oxprenolol and metoprolol may differ in their effects on hemodynamic response to hypoglycemia. This aspect of the problem requires further study under careful control in hypertensive diabetics.     

Effect of phosphodiesterase-5 inhibitors on cerebral blood flow in human beings: a systematic review

Background

Phosphodiesterase-5 inhibitors (PDE5i) are established in the treatment of erectile dysfunction and pulmonary hypertension. Agents that augment cerebral blood flow could be a potential treatment for vascular cognitive impairment. The aim of this review was to assess the published effects of PDE5i on cerebral blood flow in human beings.

Comparative studies on fatty acid synthesis, glycogen metabolism, and gluconeogenesis by hepatocytes isolated from lean and obese Zucker rats

Hepatocytes isolated from genetically obese female Zucker rats and lean female Zucker rats were compared. Hepatocytes from fed obese rats exhibited greater rates of fatty acid synthesis, more extensive accumulation of lactate and pyruvate from their glycogen stores, increased rates of net glucose utilization but produced less ketone bodies from exogenous fatty acids and had lower citrate levels than hepatocytes from lean rats. Lipogenesis was not as sensitive to dibutyryl cyclic AMP (DBcAMP) inhibition in hepatocytes from obese rats but glycogenolysis was stimulated to the same extent by this nucleotide in both preparations. Ketogenesis was less sensitive to stimulation by DBcAMP in hepatocytes from obese rats. A difference in sensitivity of lipogenesis to DBcAMP was not found when lactate plus pyruvate was added to the incubation medium, suggesting that a greater rate of glycolysis by hepatocytes from obese rats accounts for their relative insensitivity to DBcAMP. Citrate levels were elevated by DBcAMP to a greater extent in hepatocytes from obese rats. Hepatocytes prepared from lean rats starved for 48 hr were glycogen depleted and lacked significant capacity for lipogenesis and glycogen synthesis. In contrast, hepatocytes isolated from starved obese rats retained considerable amounts of liver glycogen and exhibited detectable rates of lipogenesis and glycogen synthesis. Hepatocytes prepared from starved lean rats gave faster apparent rates of lactate gluconeogenesis than hepatocytes prepared from starved obese rats. Thus, hepatocytes prepared from obese Zucker rats are more glycogenic, glycolytic, and lipogenic but less ketogenic and glucogenic than hepatocytes prepared from lean rats.     

The physiologic action of insulin on glucose uptake and its relevance to the interpretation of the metabolic clearance rate of glucose

Glucose uptake (Ru) is dependent upon the concentrations of both glucose and insulin. The metabolic clearance rate of glucose (MCRG), has been used as an in vivo measure of insulin action, because it was said to be independent of the prevailing glucose concentration. The validity of this assumption has recently been challenged. In this study, the effect of insulin concentration on the rate of glucose uptake (Ru) and on the MCRG was studied during euglycemia (5.1 +/- 0.3 mmol/L) and moderate hyperglycemia (10.4 +/- 0.5 mmol/L) in 17 experiments on nine normal ambulant volunteers. Stable plasma insulin levels were maintained with fixed infusion rates of insulin (0-300 mU/kg/h) and somatostatin (7.5 micrograms/min). At low insulin concentrations (less than 5 microU/mL) the increase in glucose uptake in response to hyperglycemia was small (5.3 +/- 2.3 mumol/kg/min). In contrast, with insulin levels more than 25 microU/mL, there was a steep rise in glucose uptake with hyperglycemia (55 +/- 3 mumol/kg/min; range: 44-74 mumol/kg/min). The metabolic clearance rate of glucose fell by an average of 32% with hyperglycemia in the studies at the lowest insulin levels (2.2 +/- 0.6 v 1.5 +/- 0.1 mL/kg/min; 0.15 greater than P greater than 0.1). There was no change in the MCRG in the subjects studied at higher insulin levels. It is concluded that (1) low concentrations of insulin are essential for the increase in glucose disposal during hyperglycemia; and (2) provided insulin levels are more than 25 microU/mL and plasma glucose less than 11 mmol/L, MCRG is independent of the plasma glucose concentration and is therefore a valid measure of insulin-mediated glucose uptake.