Digoxin disposition in obesity: Clinical pharmacokinetic investigation

Olgoxin pharmacokinetics were studied in 16 obese (mean ± SD weight, 100.2 ± 36.8 kg) and 13 control (64.6 ± 10.5 kg) subjects. all subjects had normal renal function and no other coexisting disease. After administration of 0.75 mg digoxin by intravenous intusion, multiple plasma samples obtained over the 96 hours following infusion were analyzed for digoxin concentration by radloimmunoassay. Pharmacokinetic parameters were determined by weighted iterative nonlinear least squares regression analysis. Elimination half-life ($\text{t}\text{1}\text{2}$) was not different between obese and control groups (35.6 ± 10.5 vs 41.2 ± 16.7 hours). Absolute volume of distribution (Vd) also was not different (981 ± 301 vs 937 ± 397 liters), nor was total clearance of digoxin (328 ± 82 vs 278 ± 87 ml/min). Elimination $\text{t}\text{1}\text{2}$ was significantly negatively correlated with clearance among all subjects (r = ?0.46; p < 0.01). Using percent ideal body weight (IBW) as a measure of obesity, no correlation was found between percent IBW and Vd (r = 0.03). Thus digoxin is simllarly distributed into IBW in obese and normal weight subjects, and there is no significant distribution of digoxin into excese body weight over IBW. In addition, there is no difference in total metabolic clearance or elimination half-life between obese and control subjects. Digoxin loading and maintenance dosage should be calculated on the basis of IBW, which reflects lean body mass, rather than TBW, which reflects adipose tissue weight in addition to lean body mass.     

Ibuprofen disposition in obese individuals

Eleven obese subjects (weight 114 +/- 11 kg, mean +/- SE) and 11 age-matched subjects with normal body weight (61 +/- 3 kg) were given 600 mg of ibuprofen orally after an overnight fast. Peak ibuprofen concentration was significantly decreased in obese subjects (P less than 0.02), although the time from administration to peak concentration was not different. Ibuprofen volume of distribution was increased in obese subjects, and this increased distribution correlated positively with body weight (r = 0.82; P less than 0.001). Volume of distribution corrected for body weight was decreased in obese subjects, and this decrease correlated negatively with body weight. Ibuprofen clearance was also increased in obese subjects; the increase correlated positively with body weight (r = 0.81; P less than 0.001). Since the independent variables, volume of distribution and clearance, were increased in parallel in the obese subjects, the dependent variable, elimination half-life, was unchanged. Using mean values of distribution calculated from the 2 groups, ibuprofen distribution into body weight in excess of ideal body weight was found to be approximately 0.44 times as extensive as the distribution into ideal body weight. Furthermore, ibuprofen clearance increased in parallel with the volume of distribution and total body weight. Clinically, these data indicate that in obese patients, the ibuprofen dose may be increased without changing the dose interval, in order to achieve necessary plasma concentrations.     

Dosage of antituberculous drugs in obese patients

There are no published data defining efficacious drug therapy for obese patients with active tuberculosis. Current dosage recommendations are based on total body weight (TBW); drug toxicity might result in obese patients receiving TBW doses. Peak and trough serum levels were measured for rifampin, streptomycin, ethambutol, and pyrazinamide in an obese patient (166 kg TBW, 87 kg ideal body weight (IBW] with miliary and meningeal tuberculosis. The observed drug levels and the calculated serum half-lives of these drugs were compared with the expected serum levels and serum half-lives in lean patients treated with literature-recommended doses. The observed serum levels in our obese patients were within the expected range for lean patients when dosage was based on IBW rather than on TBW. The observed cerebrospinal fluid penetrations of the drugs studied in our obese patient were similar to those reported in lean patients.     

Lidocaine disposition in obesity

Fourteen obese men (mean weight 124 ± 8 kg (± standard error of the mean), percent ideal body weight (IBW) 169 ± 10%), 11 obese women (96 ± 6 kg; 174 ± 11% IBW), 19 control men (69 ± 1 kg; 93 ± 2% IBW), and 12 control women (59 ± 2 kg; 102 ± 3% IBW), all of similar age and without clinical or laboratory evidence of cardiac or renal dysfunction, received a single 25-mg intravenous dose of lidocaine. Elimination half-life was markedly prolonged in obese compared with control men (2.69 ± 0.2 vs 1.62 ± 0.06 hour, p < 0.001) and in obese compared with control women (2.95 ± 0.1 vs 2.08 ± 0.06 hour, p <0.01). This was not the result of a change in clearance (men, obese vs control: 1,427 ± 117 vs 1,346 ± 86 ml/min, difference not significant, [NS]; women: 1,089 ± 83 vs 1,162 ± 84 ml/min, NS), but rather of an increased absolute volume of distribution (Vd) in obese men (325 ± 29 vs 186 ± 12 liters, p <0.001) and obese women (264 ± 20 vs 209 ± 15 liters, p <0.025). Vd corrected for total body weight was unchanged in obesity for both men (2.67 ± 0.22 vs 2.71 ± 0.18 1/kg, NS) and women (2.88 ± 0.31 vs 3.57 ± 0.25, NS), suggesting that lidocaine Vd increases in parallel with body weight in both sexes. Because lidocaine clearance is determined mainly by hepatic blood flow, these findings suggest that extremes of body weight do not change hepatic blood flow. However, lidocaine distribution is markedly increased in obese subjects of either sex, and is distributed to the same extent into excess body weight as into IBW. Lidocaine loading doses in obese persons should be calculated based on total body weight, but infusion rate should not be changed.     

Effect of body weight on the volume of distribution of theophylline

The volume of distribution (Vd) of theophylline and the relevant aminophylline loading dose (LD) are usually calculated on the basis of total body weight (TBW). In obese subjects it has been suggested that lean or ideal body weight (IBW) is the best predictor. In a sample of 40 acutely ill asthmatic patients (aged 22 to 78 yr, weighing 45 to 176 kg) we measured Vd and found that (1) it increases with TBW, (2) it cannot be accurately predicted from either TBW or IBW alone by a simple regression analysis. Power functions have been usefully applied in comparing the pharmacokinetics of animal species, including humans, with different body mass. In our sample, data were best fitted by the equation Vd = 1.29 TBW^0.74, which seems to take care of lean as well as obese patients. Results were confirmed (r = 0.89 between predicted and measured values) in a second independent sample of patients (aged 26 to 77 yr, weighing 38 to 167 kg). This helps to minimize the error in obtaining the target serum concentration of theophylline when giving a LD calculated from a predicted Vd value.     

Effect of body weight on the volume of distribution of theophylline

The volume of distribution (Vd) of theophylline and the relevant aminophylline loading dose (LD) are usually calculated on the basis of total body weight (TBW). In obese subjects it has been suggested that lean or ideal body weight (IBW) is the best predictor. In a sample of 40 acutely ill asthmatic patients (aged 22 to 78 yr, weighing 45 to 176 kg) we measured Vd and found that (1) it increases with TBW, (2) it cannot be accurately predicted from either TBW or IBW alone by a simple regression analysis. Power functions have been usefully applied in comparing the pharmacokinetics of animal species, including humans, with different body mass. In our sample, data were best fitted by the equation Vd = 1.29 TBW 0.74, which seems to take care of lean as well as obese patients. Results were confirmed (r = 0.89 between predicted and measured values) in a second independent sample of patients (aged 26 to 77 yr, weighing 38 to 167 kg). This helps to minimize the error in obtaining the target serum concentration of theophylline when giving a LD calculated from a predicted Vd value.     

The influence of orally administered cimetidine and theophylline on the elimination of each drug in patients with chronic airways obstruction

We studied the effect of cimetidine and theophylline on the metabolism of each drug in 19 elderly patients with stable chronic obstructive pulmonary disease. Each patient received either regular release or sustained release oxtriphylline. Cimetidine was given to some patients in both groups after steady state for theophylline was achieved. Multiple serum theophylline and cimetidine measurements were performed. Cimetidine decreased theophylline clearance by an average of 37.8% (26.2 to 46.7) for regular release and 33.4% (22.2 to 45.0) for sustained release oxtriphylline. The apparent volume of distribution was not changed; however, the half-life for theophylline was increased. As there is a linear relationship between the theophylline clearance before and after the addition of cimetidine and a linear relationship between trough and peak values before and after cimetidine, these 2 relationships may be used to predict clearance values and serum levels after cimetidine treatment when the initial values are known.     

Cimetidine impairs clearance of antipyrine and desmethyldiazepam in the elderly

Sixteen young (21-40 years) and nine elderly (65-78 years) volunteers received single intravenous doses of antipyrine on two occasions: once in the control state, and again while receiving therapeutic doses of cimetidine (300 mg every six hours). In the control state, antipyrine half-life was longer in elderly than in young subjects (16.4 vs 11.0 hours), and metabolic clearance lower (0.48 vs 0.72 ml/min/kg). However, coadministration of cimetidine prolonged antipyrine half-life to a similar extent in elderly and in young groups (150 and 153 per cent of control) and reduced metabolic clearance to a similar extent in both (79 vs 69 per cent of control) groups. Three young and six elderly volunteers received a single 15 mg oral dose of clorazepate, a precursor of desmethyldiazepam, with and without cimetidine. As in the case of antipyrine, cimetidine prolonged desmethyldiazepam half-life similarly in young and elderly groups (175 vs 164 per cent of control) and similarly reduced metabolic clearance (51 vs 65 per cent of control). The elderly population may already have an impaired capacity to oxidize drugs. This capacity is further impaired by coadministration of cimetidine.     

The metabolic clearance rate of corticosterone in lean and obese male Zucker rats

The obese Zucker rat is an animal model of human juvenile-onset obesity. These rats exhibit numerous endocrine and metabolic abnormalities. Adrenalectomy of obese rats has been shown to reduce or reverse several of these abnormalities, thereby implying that corticosterone may contribute to the expression of obesity in this animal. Furthermore, it has been shown that the circadian rhythm of plasma corticosterone is disturbed in obese Zucker rats resulting in elevated morning plasma corticosterone concentrations in obese rats as compared to lean rats. In a effort to better elucidate the mechanism of the elevated morning levels of plasma corticosterone, the metabolic clearance rate of corticosterone was determined in the morning for lean and obese male Zucker rats (12 to 20 weeks). Additionally, the biliary and urinary excretion of labeled corticosterone and/or its metabolites were determined. The metabolic clearance rate of corticosterone was significantly greater in obese rats than in their lean counterparts. Both the metabolic clearance rate and the volume of compartments significantly correlated with body weight. No correlation was found between body weight and the elimination rate constant. The increased metabolic clearance rate of obese rats appeared to be due to an increase in the physiologic distribution of corticosterone and not to an alteration in the enzymes responsible for corticosterone metabolism. It appears that the metabolic clearance rate of corticosterone in obese Zucker rats does not contribute to elevated morning concentrations of plasma corticosterone previously observed in these animals. It suggests that the adrenal corticosterone secretion rate must actually be greater than one would expect from the plasma corticosterone concentrations alone.     

Impact of weight loss on cortisol secretion in obese men with and without metabolic syndrome features

BACKGROUND AND AIM: Disturbances in cortisol metabolism have been associated with obesity and metabolic syndrome development. The aim of this study was to evaluate the effect of weight loss induced by an energy-restricted diet on postprandial cortisol secretion in obese men with and without metabolic syndrome features. METHODS AND RESULTS: Twelve obese men (BMI: 32.5-36.2 kg/m2), six without and six with at least three markers of metabolic syndrome, and six lean men (BMI: 22.2-24.9 kg/m2) participated. Plasma cortisol was measured at fasting and at 30 min intervals for 3h after standard breakfast intake. Obese volunteers repeated those measurements after weight loss induced by a 10-week hypocaloric balanced diet. Fasting (p = 0.002) and postprandial (p = 0.014) cortisol secretions in obese men were statistically lower than in lean subjects. The slimming program produced a -0.9 kg per week mean weight reduction with no differences between both groups (p = 0.297). After weight loss, postprandial cortisol secretion increased in volunteers with (p = 0.028) and without metabolic syndrome manifestations (p = 0.043), as compared to baseline, achieving values near to those of controls. Cortisol levels negatively correlated with body weight (r = -0.61; p < 0.001). CONCLUSIONS: Therefore, the effect of weight loss on cortisol metabolism appeared to be mediated by changes in body weight, which were apparently not affected by the occurrence of metabolic syndrome features.     

Sedation for Endoscopy

Abstract  In order to examine the investigators' clinical suspicion that Vietnamese patients were more sensitive to the sedative effects of midazolam than were Caucasians, the pharmacokinetics of a single, weight-adjusted intravenous dose of midazolam (0.05 mg/kg) were compared in a group of healthy Caucasian and Vietnamese male volunteers. The Vietnamese group ( n =8) had a significantly lower height, lean body mass and mean weight (59.8±5.5 vs 72.1±8.1 kg, respectively) compared with the Caucasian group ( n =8). No significant differences were found between the Vietnamese and Caucasian groups with regard to distribution half-life of midazolam (8.38±13.1 vs 1.49±0.63 min, respectively), elimination half-life (2.49±1.80 vs 1.48±0.66 h, respectively), clearance (4.93±1.31 vs 5.90±2.12 mL/min per kg, respectively), steady state volume of distribution (0.863±0.497 vs 0.530±0.132 L/kg, respectively) or percentage of unbound drug in plasma (4.89±0.74 vs 4.11±1.08, respectively). This suggests that dosage of midazolam in Vietnamese should be based on total body-weight. Two Vietnamese subjects who were brothers had marked elevation of distribution half-life and initial volume of distribution and lesser elevations in elimination half-life and volume of distribution at steady state. This suggests that the known subgroup of subjects who demonstrate dyshomogeneity in midazolam volume of distribution may be genetically determined.     

Energy Expenditure in Lean and Obese Diabetic Patients Using the Doubly Labelled Water Method

Obesity is a common problem among Type 2 diabetic patients. To investigate the role of energy expenditure in the maintenance of obesity in diabetic subjects, total energy output was measured during weight stability in 23 diabetic patients: 8 lean, 5 overweight, and 10 obese. Free living total energy expenditure was measured over 14 days using doubly labelled water method, resting metabolic rate by indirect calorimetry, and urinary energy losses were assessed. Total energy output was higher in the obese (13.66 ± SD 3.18 MJ 24 h^?1) than normal weight patients (10.84 ± 2.02 MJ 24 h^?1; p < 0.05); 11.96 ± 2.51 MJ 24 h^?1 in the overweight. None of the lean but four of the obese had total energy output > 16 MJ 24 h^?1. Urinary energy losses accounted for only 0.6% of total energy output in lean, 2.8% in overweight, and 3.1% in obese. Resting metabolic rate was significantly higher in obese (7.47 ± 1.69 MJ 24 h^?1) compared to lean (5.87 ± 1.07; p < 0.05) and resting metabolic rate correlated with lean body mass (r = 0.8, p < 0.001). Thermogenesis plus physical activity was substantial and not lower in the obese (5.77 versus lean 4.97 MJ 24 h^?1). The mean ratio of total energy expenditure to resting metabolic rate was in the moderate exercise category and similar in lean (1.87) and obese (1.80). Resting metabolic rate, total energy expenditure, and thermogenesis and physical activity were similar in all three groups when corrected for differences in lean body mass. In conclusion, high energy intake and not reduced energy expenditure is the major cause of the maintenance of obesity in diabetic patients. Overall there was no evidence of an energy deficit in the obese. This work emphasized the need for increased patient nutritional education to control energy intake.     

Serum insulin and blood pressure in an obese population

Serum insulin has been implicated as a determinant of blood pressure (BP) level in obese hypertensive individuals. We examined the relationships among fasting insulin, mean arterial pressure (MAP), body composition, and fat distribution in 204 subjects unselected for glucose tolerance. All met the criteria of taking no oral hypoglycemic agents, insulin or antihypertensive medications. 95 percent were considered obese and 78 percent were female. Mean age was 39 years (range 15-71), percent ideal body weight (IBW) 171 percent (109-332), BP 125/81 mmHg (80-181/50-110) and fasting insulin 44 microU/ml (4-196). Lean body mass (LBM) and body fat were measured by tritium dilution. The correlation coefficient between insulin and MAP was 0.32 (P less than 0.0001). Both insulin and MAP correlated highly with percentage IBW, percentage body fat, fat mass, LBM, body build and upper fat pattern. Controlling for these variables simultaneously eliminated the association between insulin and BP. By contrast, the correlations between MAP and measures of body composition and fat distribution retained significance after controlling for insulin level. These findings suggest that measures of body composition and fat distribution have a relationship with BP that is not entirely accounted for by serum insulin level, and the relationship between serum insulin and BP is indirect and largely accounted for by their mutual association with measures of body composition and fat distribution.     

Effect of cimetidine on the pharmacokinetics and pharmacodynamics of quinidine

The influence of Cimetidine (1.2 g/day for 7 days) on the disposition and pharmacodynamic effects of a single oral dose of qulnidine was studied in 6 normal volunteers. Cimetidine reduced the mean apparent oral clearance of quinidine (± standard error of the mean) from 25.5 ± 2.7 to 16.2 ± 1.4 liters/h (p < 0.05). This was reflected in a 55% (range 30 to 109) increase in the mean half-life from 5.8 ± 0.2 to 9.0 ± 0.6 hours (p < 0.05). Peak quinidine plasma concentrations and times to peak were also increased (p < 0.05). Plasma protein binding and urinary excretion of quinidine were unchanged by Cimetidine treatment. Alterations in the pharmacokinetic variables of quinidine were mirrored in simultaneously measured electrocardiographic parameters. Changes in Q-T, rate-corrected Q-T, QRS, and R-R intervals after a single oral dose of quinidine sulfate (400 mg) were significant. Treatment with cimetidine potentiated these pharmacodynamic changes, but failed to achieve significant differences from quinidine alone. Thus, cimetidine impairs the elimination of oral quinidine in normal volunteers. This interaction may lead to quinidine toxicity in patients in whom Cimetidine is concomitantly administered.     

Disposition and toxicity of amphotericin-B in the hyperlipidemic Zucker rat model

The pharmacokinetics and toxicity of the lipophilic antifungal agent, amphotericin-B (AmpB), were studied in the hyperlipidemic obese rat model and compared with lean litter-mates. Serial blood samples were obtained for 36 h following a single intravenous infusion of AmpB (1.2 mg/kg) with pre- and post-drug measurements of renal function. Although triglyceride, cholesterol, HDL-cholesterol and LDL + VLDL-cholesterol levels were elevated in the obese compared with lean rats, protein: lipoprotein ratios were similar. There was a 2-fold increase in the area under the serum concentration-time curve of AmpB in obese rats compared to lean litter-mates (15,600 +/- 6900 v. 7800 +/- 2900 ng. h/ml; P less than 0.05); no differences in elimination rate constants were found between groups. Weight-corrected volume of distribution and total body clearance were significantly lower in obese compared with lean rats; no differences were found in absolute clearance or volume. Kidney levels of AmpB were markedly increased in obese versus lean rats. Similarly, kidney to serum ratios of AmpB were greater in obese compared with lean rats (152 +/- 113 v. 41 +/- 23; P less than 0.001). There was a significant decline in the creatinine clearance from baseline in the obese rats coupled with a rise in serum creatinine; no differences were found in lean rats. Similarities in absolute pharmacokinetic variables and protein: lipoprotein ratios suggest differences in AmpB disposition and toxicity are a result of differences in lipoprotein-mediated transport mechanisms between obese and lean rats.     

Gastric inhibitory polypeptide responses to nutrients in Caucasians and American Indians with obesity and noninsulin-dependent diabetes mellitus

Serum gastric inhibitory polypeptide (GIP), insulin, and glucose responses to either a 75-g oral glucose challenge or a 500-cal liquid test meal were determined in 141 Caucasians and American Indians. The Caucasians were normal weight, averaging 101 +/- 3% (+/-SEM) ideal BW (IBW), or were obese (168 +/- 21% IBW) and had normal glucose tolerance (n = 77), impaired glucose tolerance (IGT; n = 12), or noninsulin-dependent diabetes mellitus (NIDDM; n = 19). The American Indians were all obese (144 +/- 6% IBW) and had either normal glucose tolerance (n = 22) or NIDDM (n = 11). In all study subjects, including obese individuals with and without glucose intolerance, diabetic patients both thin and obese, and lean subjects with impaired glucose tolerance, fasting serum insulin and GIP, and incremental glucose, insulin, and GIP were greater than they were in normal lean subjects, especially during the first hour of the tests. Obese subjects and diabetic patients exceeded lean normal subjects by up to 620% for glucose, up to 640% for insulin, and up to 360% for GIP during the first hour after glucose ingestion or the test meal. Exceptions were two groups with the most severe diabetes in whom incremental insulin values after oral glucose were only 70% (thin Caucasians) and 110% (obese Indians) that of lean normal subjects. The smallest differences in GIP responses occurred between lean normal subjects and obese nondiabetic Caucasians tested with either a meal or oral glucose, whereas American Indians consistently had the greatest insulin and GIP responses to the tests. High fasting GIP and exaggerated GIP increments in response to nutrients could be attributed to neither obesity nor diabetes alone nor to the type of nutrient used to stimulate its release, but, instead, may be genetic or dietary in origin or may be due to other as yet unidentified factors. High basal GIP and exaggerated nutrient-stimulated GIP release were associated with hyperinsulinemia, except in the most severe diabetic patients. These observations suggest that exaggerated GIP release, along with a greater rise in serum glucose in response to nutrients, may play a role in the pathogenesis of the hyperinsulinemia of obesity and early NIDDM.     

Abnormalities of islet B-cell function, insulin action, and fat distribution in women with histories of gestational diabetes: relationship to obesity

Although obese women with histories of gestational diabetes mellitus (former GDM) are highly predisposed to develop noninsulin-dependent diabetes mellitus (NIDDM), lean former GDM women are less predisposed. To explore reasons for this difference, we performed measures of islet B-cell function and insulin action in eight lean former GDM women [ideal body weight (IBW), 107 +/- 2% (mean +/- SEM)], 11 obese former GDM (IBW, 161 +/- 11%), and 19 normal women subjects who were individually pair-matched to former GDM for % IBW and age. The first phase (0-10 min) insulin secretory response to iv glucose was significantly lower in both lean and obese former GDM compared to that in normal women (3,480 +/- 548% vs. 8,234 +/- 1,337% basal . min and 3,444 +/- 682 vs. 10,251 +/- 2,465). The second phase (10-60 min) insulin response to glucose was also significantly lower in lean former GDM women and tended to be lower in obese former GDM women compared to that in their respective controls. Insulin action was assessed by the insulin sensitivity index (SI) using Bergman's minimal modeling technique. SI values in lean former GDM women were similar to those in their controls (4.42 +/- 1.3 X 10(-4) ml min-1 microU-1 vs. 5.19 +/- 1.2 X 10(-4). In contrast, SI values in obese former GDM women were significantly lower than those in their controls (0.77 +/- 0.28 X 10(-4) vs. 2.04 +/- 0.43 X 10(-4). To assess whether differences in fat distribution and fat cell size were associated with these differences in insulin sensitivity, the waist to thigh circumference ratio, the waist to hip ratio, and abdominal fat cell diameter were measured. All three were significantly greater in the obese former GDM women than in controls. Thus, an abnormal central distribution of adiposity appears to be associated with the insulin action defect in obese former GDM women. We conclude that both lean and obese former GDM women have insulin secretion defects. Although a modest insulin action defect in lean former GDM women may have been missed by this technique, only in the obese former GDM women, who have a higher risk for future NIDDM, was an insulin action defect demonstrable. Thus, impairments of both insulin secretion and insulin action may be necessary to cause a marked predisposition toward NIDDM.     

Plasma concentrations of alpha-MSH, AgRP and leptin in lean and obese men and their relationship to differing states of energy balance perturbation

OBJECTIVE: A great deal of attention has focused on the central role of alpha melanocyte-stimulating hormone (alpha-MSH) and its antagonism at the melanocortin-4 receptor (MC4R) by agouti related protein (AgRP) in the regulation of energy balance. However, very little is known regarding the function of circulating AgRP and alpha-MSH in humans. We aimed to determine whether circulating alpha-MSH and AgRP are responsive to long-term perturbations in energy balance, in a manner consistent with their central putative functions. DESIGN AND MEASUREMENTS: Circulating alpha-MSH, AgRP and leptin were measured in both lean (n = 11) and obese (n = 18) male volunteers, some of whom (lean n = 11, obese n = 12) were then allocated one of two weight-loss dietary strategies to achieve about 5% weight loss. This was achieved by either total starvation (for 4-6 days) for rapid weight loss or a very low calorie diet (VLCD, 2.6 MJ/day) (11-12 days) for less rapid weight loss, in both the lean and obese volunteers. RESULTS: At baseline, prior to any weight loss both plasma alpha-MSH (15.8 +/- 1.2 vs. 5.8 +/- 1.0 pmol/l +/- SEM; P < 0.001) and AgRP (49.4 +/- 2.4 vs. 10.1 +/- 0.9 pg/ml +/- SEM; P < 0.001) were elevated in obese subjects compared with lean. In both cases this correlated closely with fat mass (P < 0.001), percentage body fat (P < 0.001) and leptin (P < 0.05). Plasma AgRP increased significantly during a 6-day fast in lean individuals (11.1 +/- 1.6 vs. 21.6 +/- 3.1 pg/ml +/- SEM; P < 0.05) but not in the VLCD subjects or in the obese, while alpha-MSH was not affected by any changes in energy balance in either the lean or the obese volunteers. CONCLUSION: We show a difference in alpha-MSH and AgRP in lean and obese subjects that correlates closely with body fat at baseline. We demonstrate an increase in plasma AgRP during a 6-day fast in lean individuals that is coincident with a decrease in plasma leptin. This increase in AgRP was not due to weight loss per se as there was no change in AgRP as a result of the same weight loss in the VLCD intervention in lean individuals. The source of the increase in plasma AgRP and its physiological function in the periphery remains to be elucidated but we suggest that the dynamics of the change in plasma leptin may determine the elevation in fasting plasma AgRP in lean subjects.     

Shifting perspectives – interplay between non-alcoholic fatty liver disease and insulin resistance in lean individuals

Non-alcoholic fatty liver disease(NAFLD) has become a significant public health burden affecting not only obese individuals but also people with normal weight.As opposed to previous beliefs,this particular subset of patients has an increased risk of all-cause mortality and worse outcomes than their obese counterparts.The development of NAFLD in lean subjects seems to be interconnected with metabolic phenotype,precisely visceral fat tissue,sarcopenia,and insulin resistance.Here,we summarize available data focusing on the co-dependent relationship between metabolic phenotype,insulin resistance,and development of NAFLD in lean individuals,suggesting more appropriate tools for measuring body fat distribution for the screening of patients at risk.     

Metabolic studies in human obesity during overnutrition and undernutrition: thermogenic and hormonal responses to norepinephrine

Overfeeding increases the thermogenic response of norepinephrine (NE) in normal but not in certain genetically obese rodents. It has been suggested that human obesity may be associated with a similar thermogenic defect. To determine whether there are differences in the thermogenic sensitivity to NE in human obesity, energy expenditure in response to graded infusions of NE (0.05, 0.10, 0.15, 0.20 micrograms/min/kg fat-free mass) was measured in six lean and six obese subjects (9.5 +/- 1.8 v 36.3 +/- 3.8% body fat P less than 0.005). Resting metabolic rate (RMR), thermogenic response to NE, and thermogenic response to exercise were measured during weight maintenance and during the third week of feeding 1000 extra Kcal/d in the lean and obese subjects. These components of energy expenditure were also measured in the obese subjects during the third week of a 589 Kcal/d diet. Resting metabolic rate increased during overfeeding in lean (6.6%, P less than 0.05) but not in the obese subjects (2.7%, P = NS) and fell during underfeeding in the obese (-9.1%, P less than 0.02). There was a logarithmic increment above baseline in VO2 v plasma NE concentration during the NE infusions (r = 0.75, P less than 0.005) in lean subjects which was unaltered by overfeeding. The obese exhibited equivalent VO2 responses to NE to that measured in the lean. Supine plasma NE concentrations were lower but metabolic clearance rates (MCR) of NE were similar in the obese compared to lean subjects during both weight maintenance and overfeeding. Overfeeding minimally increased plasma concentration but not MCR of NE in both groups. The thermogenic response to exercise was similar in the lean and obese subjects and was unaltered by overfeeding or underfeeding. The increments in plasma glycerol and free fatty acid in response to the NE infusions were proportional to the total fat mass of each individual and were greater in the obese subjects. Overfeeding partially suppressed the lipolytic response to NE in both groups and underfeeding increased the lipolytic response in the obese. There are no differences in thermogenic responses to NE in human obesity to account for excessive fat deposition. Overfeeding does not increase the thermogenetic responses to NE in humans as has been reported in small mammals.