'Obesity paradox' misunderstands the biology of optimal weight throughout the life cycle.

The 'obesity paradox' refers to observations that run counter to the thesis that normal weight (BMI 18.5-24.9 g/m(2)) provides the lowest mortality and higher weight is associated with greater mortality. We argue that the weight of lowest mortality is influenced by aging and chronic disease, with mortality advantage extending into the overweight and even class I obese ranges under some circumstances. A focus on quality nutrition, physical activity, fitness, and maintaining function in these weight ranges may be preferable to a focus on intentional weight loss, which has uncertain effects. The 'obesity paradox' is no 'paradox' if one defines and interprets 'ideal' weight appropriately.

Does intra-abdominal adipose tissue in black men determine whether NIDDM is insulin-resistant or insulin-sensitive?

Insulin resistance in black Americans with non-insulin-dependent diabetes mellitus (NIDDM) is found in only 60% of those with a body mass index (BMI) of < 30 kg/m2, suggesting that NIDDM can occur independent of peripheral insulin resistance. When insulin resistance is present, it is not necessarily correlated with obesity. Numerous studies have shown that increased amounts of intra-abdominal adipose tissue are associated with various metabolic abnormalities. We therefore investigated whether the occurrence of insulin resistance in black NIDDM men could be explained by the pattern of body adipose tissue distribution rather than total adiposity. Twenty-two near-normoglycemic black men (fasting plasma glucose [mean +/- SD] = 104 +/- 10 mg/dl, HbA1c = 4.6 +/- 0.78%, age 48.9 +/- 9.2 years, and BMI 26.5 +/- 2.4 kg/m2) were studied. The euglycemic insulin clamp with 1 mU.kg-1.min-1 insulin infusion and D-[3-3H]glucose was used to measure insulin action. Whole-body computed tomography with 22 scans was used to determine body composition. Total body adipose tissue was 19.6 +/- 7.51, and the percentage of body fat was 27 +/- 7. Glucose disposal ranged from 2.5 to 8.1 mg.kg-1.min-1 (10 men were insulin-sensitive and 12 were insulin-resistant). There was a strong inverse correlation between glucose disposal and the proportion of total adipose tissue in the intra-abdominal region (r = -0.78, P < 0.001), while there was no correlation between glucose disposal and total muscle volume, BMI, total adipose tissue volume, or total subcutaneous adipose tissue volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic abnormalities in bulimia nervosa.

Resting metabolic rate was measured in a group of 22 women of normal body weight with bulimia nervosa and in 19 age-, sex-, and weight-matched control subjects. Mean resting metabolic rate of patients was significantly lower than that of controls (5162 +/- 928 vs 5636 +/- 449 kJ/24 h [1229 +/- 221 vs 1342 +/- 107 kcal/24 h]), as was mean fasting blood glucose level (4.0 +/- 0.6 vs 4.6 +/- 0.6 mmol/L). Mean basal thyrotropin level was significantly lower in patients than controls, but other thyroid indexes did not differ. There were no group differences in body fat mass, fat cell size, or lipoprotein lipase activity. These data suggest that there is a disturbance in energy regulation in bulimia nervosa. However, the origins and role of this disturbance in the pathophysiology of bulimia are unclear.

Angiotensin II receptors in human preadipocytes: role in cell cycle regulation.

The role of angiotensin II (AII) in human preadipocyte physiology has been investigated in primary cultures from human adipose tissue. Receptor binding studies indicated that human preadipocytes express a high affinity AII binding site of the AT1 subtype, as binding of 125I-labeled [Sar1,Ile8]AII was rapid, saturable, and specific. As AII has previously been demonstrated to affect the cell cycle in adrenal and cardiac cells, the effect of AII on regulation of cycle progression was examined in human preadipocytes. Stimulation of preadipocytes with AII resulted in G1 phase progression of the cell cycle, as determined by flow cytometric analysis. AII treatment was associated with induction of expression of the messenger RNA for the cell cycle regulatory protein cyclin D1 in a dose-dependent manner. Pretreatment of cells with subtype-selective AT receptor ligands before AII stimulation indicated that the cyclin response was mediated via the AT1 receptor. The identity of the cells as preadipocyte was verified by culture in a defined differentiation medium, observing both leptin message expression and triglyceride accumulation by flow cytometry. These findings indicate that AII has early, receptor-mediated effects on cell cycle progression in human preadipocytes that may contribute to differentiation to the adipocyte phenotype.

Autocrine regulation of human preadipocyte migration by plasminogen activator inhibitor-1.

One of the initial stages of adipogenesis is migration of preadipocytes of mesenchymal origin into cell clusters to form primitive fat organs. The serine protease inhibitor plasminogen activator inhibitor-1 (PAI-1) is synthesized and released from human adipose tissue ex vivo and regulates smooth muscle and endothelial cell migration in vitro, but its role in adipose tissue is not known. We investigated the role of PAI-1 in cultures of human preadipocytes from men and women of various ages and body mass indexes. Human preadipocytes expressed the messenger ribonucleic acid for PAI-1 and released significant quantities of PAI-1 protein into the medium. As PAI-1 regulates motility through the interaction of vitronectin with its receptor, the integrin alphaVbeta3, we identified this receptor in human preadipocytes. Flow cytometric analysis indicated that human preadipocytes express the vitronectin receptor alphaVbeta3 in a similar pattern as human umbilical vein endothelial cells. Functional studies indicated that active, but not latent, PAI-1 inhibited preadipocyte attachment to vitronectin with an IC(50) of 13.3 nmol/L, and preincubation of vitronectin-coated Transwells with active PAI-1 prevented preadipocyte migration. Vitronectin was identified in homogenates of the stromal-vascular fraction of human adipose tissue, but was absent from human adipocytes and cultured preadipocytes. These data indicate that human preadipocyte migration is regulated through the endogenous expression of PAI-1 and alphaVbeta3 integrin, a novel autocrine mechanism for potentially regulating cell cluster formation in adipogenesis.

Synthesis and secretion of plasminogen activator inhibitor-1 by human preadipocytes.

To further investigate the role of plasminogen activator inhibitor-1 (PAI-1) in adipose tissue physiology, the production and regulation of PAI-1 was determined in primary cultures of human preadipocytes. When expressed as production per cell and cultured under identical conditions, human preadipocytes from both visceral (omental) and sc depots of lean and obese individuals released significant, yet similar, amounts of PAI-1 protein into the conditioned medium. High steady-state PAI-1 messenger RNA (mRNA) concentrations were observed in visceral and sc preadipocytes, with the relative level of expression equivalent to beta-actin mRNA. Tumor necrosis factor alpha significantly decreased PAI-1 production in a concentration-dependent manner in both visceral and sc cultures, whereas transforming growth factor beta significantly elevated PAI-1 production, but only in sc preadipocytes from obese individuals. Addition of insulin had no effect on antigen levels in conditioned medium of preadipocyte cultures. Stimulation of the preadipocyte cultures with a defined medium resulted in differentiation to the adipocyte phenotype, as determined by flow cytometric analysis, verifying the cultures as human preadipocyte. These studies are the first to observe significant PAI-1 mRNA expression and protein production in primary cultures of a human adipose tissue cellular component, and they suggest that nascent adipocytes contribute significantly to the elevated plasma PAI-1 observed in obesity.

Liver pathology and the metabolic syndrome X in severe obesity.

The metabolic syndrome X, characterized by insulin resistance, dyslipidemia, hypertension, and a male, visceral distribution of adipose tissue, is associated with increased morbidity and mortality from several prevalent diseases, such as diabetes, cancers, myocardial infarction, and stroke. Because the liver has a central role in carbohydrate, lipid, and steroid metabolism, we investigated the relationships between liver pathology and the metabolic syndrome. Blood chemistry, anthropometry (waist/hip circumference ratio), and intraoperative routine knife biopsies of the liver were obtained in 551 (112 men) severely obese patients (body mass index, 47 +/- 9; mean +/- SD) undergoing antiobesity surgery. Steatosis was found in 86%, fibrosis in 74%, mild inflammation or steatohepatitis in 24%, and unexpected cirrhosis in 2% (n = 11) of the patients. The risk of steatosis was 2.6 times greater in men than in women (P < 0.0001). With each addition of 1 of the 4 components of the metabolic syndrome, elevated waist/hip ratio, impaired glucose tolerance, hypertension, and dyslipidemia, the risk of steatosis increased exponentially from 1- to 99-fold (P < 0.001). Fibrosis correlated with steatosis (r = 0.56; P < 0.0001), whereas patients with diabetes or impaired glucose tolerance had a 7-fold increased risk of fibrosis (P < 0.0001). Diabetes, steatosis, and age were all significant indicators of cirrhosis, whereas inflammation was only associated with age. We conclude that the metabolic syndrome via impaired glucose tolerance is strongly correlated with steatosis, fibrosis, and cirrhosis of the liver.

Overview of surgical techniques for treating obesity.

Nonsurgical methods fail to maintain clinically significant weight loss greater than or equal to 5 y in severely obese patients. Vertical banded gastroplasty and Roux-Y gastric bypass are the main operations for obesity. Modifications of intestinal bypass reserved for special cases require particular expertise in long-term management. Operations function by inducing satiety, nimiety, or aversion. Optimal weight loss or goal weights have not been defined and outcome predictors are inadequate. Results depend more on motivation and behavior than on metabolic, gastrointestinal, or technical factors. New approaches such as adding vagotomy or using inflatable cuffs to adjust outlet size in gastroplasty or modifying outlets or segment lengths in gastric bypass might improve long-term results. A staged approach to surgical treatment of obesity is proposed. Surgery will persist as a viable treatment alternative for severe obesity until effective preventive measures are taken to reduce the prevalence of this serious disease.

Refeeding after a fast in rats: effects on small intestinal enzymes.

The effect of resuming food intake after a period of starvation (refeeding) on the specific activities of selected rat intestinal enzymes was determined. The rate of weight gain was higher in refed animals than in control animals, without a difference in food intake. Fasting caused intestinal atrophy which reversed rapidly on refeeding. Fasting decreased the specific activities of sucrase, maltase, and galactokinase, but did not affect the specific activities of hexokinase, pyruvate kinase, or crypt thymidine kinase. Sucrase, maltase, hexokinase, pyruvate kinase, and thymidine kinase specific activities all rose above control values during refeeding. The overshoot in intestinal enzyme specific activities may help promote the rapid weight gain observed in refed rats and is an integral part of the total adaptation to fasting and refeeding.

Assessment of quality of life before and after surgery for severe obesity.

Quality of life is poor in obese people because of poor physical health and mental well-being and impaired psychosocial functioning. Obese people perceive discrimination and prejudice against them as their heaviest burden. Reports of absence of psychopathology in obese people reflect adaptation to chronic disease or failure of assessment instruments to detect disturbances. We present information on the extraordinary suffering and perceived discrimination of obese people and discuss econometric assessment of quality of life. The Swedish national population study of obese subjects (SOS) is presented as well as studies of effects of surgical weight loss on quality of life. Most studies lack adequate controls and extrapolations from surgical populations are uncertain. Psychosocial factors are important predictors of outcome in terms of physical as well as mental health. Operated patients with significant weight loss after surgery demonstrate dramatic improvement in quality of life. This alone justifies treating severely obese patients surgically.

Modification of weight gain by an alpha-glucosidase inhibitor during refeeding in rats.

In rats, the period of refeeding after a fast is associated with accelerated weight gain without a concomitant increase in food intake. In this study the alpha-glucosidase inhibitor, acarbose, was used to delay carbohydrate absorption in normal adult rats, and the effects on body weight, food intake, and intestinal enzyme activities were determined. Refeeding with acarbose in the food (500 mg/kg) reduced the rate of weight gain compared to refeeding without acarbose but did not change food intake. Acarbose also lowered midjejunal mass and blunted the refeeding-induced rise in certain brush border disaccharidase and intracellular glycolytic enzymes. However, acarbose refed rats still had accelerated weight gain compared to nonfasted rats, implying that the refeeding response was not totally abolished. These studies suggest that inhibition of carbohydrate absorption during refeeding might have a role in the maintenance of diet-induced weight loss.

Refeeding after fasting in the rat: energy substrate fluxes and replenishment of energy stores.

Rats were fasted and refed and concentrations of plasma glucose, glycerol, triglyceride, insulin, and glucagon as well as glucose kinetics after injection of labeled glucose and glycerol were determined. In addition, concentrations and synthesis in vivo (from tritiated water) and in vitro of glycogen, triglycerides, and protein were followed in liver, muscle, and adipose tissues. The refeeding state after fasting was characterized by a decrease in glucose and triglyceride concentrations in plasma. Glucose turnover rate was increased. Protein losses were repleted, first in the liver then in muscle tissue. Synthesis of glycogen and lipid increased above control in liver and adipose tissue. These results are compatible with an increased outflux during refeeding of different energy substrates from plasma into the depleted protein and energy stores to an extent causing lower concentration of these substrates. Such phenomena might be of importance for energy intake regulation during the phase.

Arterial cholesterol and DNA contents in relation to serum lipids and apolipoproteins. Studies on cystic artery biopsies.

Though various relationships between serum lipoprotein levels and risk for atherosclerotic disease have been shown there are only a few studies on the relationships between serum lipoprotein levels and the lipid contents of the arterial wall. This study presents cholesterol and DNA contents of arterial tissue from biopsies of the cystic artery in 23 patients with uncomplicated cholecystolithiasis. Serum levels of cholesterol, triglycerides, alphalipoprotein cholesterol, apoA-I, A-II and B were determined, and the relationships between artery and serum variables were calculated. There was a positive correlation between serum apoB and the arterial cholesterol, normalized to the DNA contents (r = 0.43, P less than 0.05). There was a tendency towards an inverse correlation between the alpha-lipoprotein cholesterol levels and the arterial cholesterol (r = 0.39, P less than 0.10). There were no significant correlations between serum apoA-I or A-II and the arterial cholesterol contents. These data indicate that deposition of cholesterol in the arterial wall is related to the serum level of apoB, with higher levels of arterial cholesterol at higher serum levels of apoB. Earlier observations of an inverse correlation between alphalipoprotein cholesterol and arterial cholesterol could, however, not be conclusively confirmed.U

Body fat topography as an independent predictor of fatty liver.

Abdominal (truncal) fat distribution reflected by an elevated waist to hip ratio (WHR) predicts metabolic abnormalities such as diabetes and dyslipidemia as well as hypertension and stroke, all of which are associated with obesity. The pathogenesis is not known, although elevated splanchnic serum free fatty acid levels and reduced hepatic insulin clearance have been implicated. WHR and body fat (BF) by 40K-counting and 3H2O were measured before liver biopsy during antiobesity surgery in 68 severely obese women (body mass index [BMI], 48.9 +/- 1.1 SEM) and 15 men (BMI, 49.0 +/- 3.1) without histories of liver disease, diabetes, or hepatotoxic exposure. Biopsies were graded for fat content semiquantitatively (0 to 4+) by the hepatologist who was blinded to the patients' clinical characteristics. All 15 men had fatty infiltration (score, 2.5 +/- 0.3 v 1.4 +/- 0.1 in women; P < .001). The correlation between WHR and liver fat was .44 (P < .0005), while BF (-.16), weight (.15), or BMI (.04) did not correlate significantly with steatosis (all NS). As expected, percentage body fat (BF%) was greater in women than in men (40.3 +/- 0.8 kg v 33.9 +/- 2.0, P < .007), and accordingly liver fat was inversely related to BF% (r = -.32, P < .002). Steatosis was significantly greater in 14 men (2.5 +/- 0.3) than in 20 women (1.7 +/- 0.3, P < .04) matched for BF%. In multiple regression analysis R2 = .49, P < .0001), WHR and sex accounted for the variance in liver fat content without any further contribution from weight, BMI, BF, or BF%.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of castration on adipose tissue growth and regrowth in the male rat.

Adipose tissue has been found to regrow in the male rat following surgical removal (lipectomy) of inguinal subcutaneous depots, but the degree of regrowth has varied widely across experiments. It is possible that at least part of the disparity of previous findings occurred because of differences among the experiments in the testicular integrity of experimental animals. To address this possibility, the present study examined effects of castration on adipose tissue regrowth in rats treated either as weanlings or as young adults. Male Sprague-Dawley rats, at either 4 or 15 weeks of age, were subjected to one of four surgical procedures: bilateral lipectomy of the inguinal subcutaneous depots; castration; lipectomy and weight gain, but castrated rats achieved a higher ratio of adipose weight to body weight than noncastrated rats. In rats lipectomized but not castrated at 15 weeks of age, partial regeneration and a small increase in growth of noninguinal subcutaneous adipose tissue combined to produce substantial restoration of adipose mass. The same surgery in 4-week-old rats did not result in significant restoration because growth of noninguinal subcutaneous adipose tissue was reduced. In rats that were both castrated and lipectomized, regrowth of adipose tissue was substantial regardless of age at time of surgery. Thus, castration is seen to impede body weight gain while sparing ordinary growth of adipose tissue and facilitating regrowth of adipose tissue following lipectomy. Since adipose tissue regrowth varied with age only in noncastrated rats, it appears to be facilitated as well by testicular maturation.

Single-cell recording from the brain of freely moving monkeys.

Single-cell recording from the brain of non-human primates has traditionally been performed in monkeys seated in a primate chair. However, this arrangement makes long-term recordings difficult, causes stress that may confound the data, and prevents the manifestation of natural behaviors. Extending our previous neurophysiological studies in non-human primates (Ludvig et al. Brain Res. Protocols 2000;5:75-85), we have developed a method for recording the electrical activity of single hippocampal neurons in freely moving squirrel monkeys (Saimiri sciureus). The recording sessions lasted for up to 6 h, during which the monkeys moved freely around on the walls and the floor of a large test chamber and collected food pellets. Stable action potential waveforms were readily kept throughout the sessions. The following factors proved to be critical in this study: (a) selecting squirrel monkeys for the experiments, (b) using a driveable bundle of microwires for the recordings, (c) using a special recording cable, (d) implanting the microwires into the brain without causing neurological deficits, and (e) running the recording sessions in a special test chamber. The described method allows long-term extracellular recordings from the brain of non-human primates, without the stress of chairing, during a wide range of natural behaviors. Using this model, new insights can be obtained into the unique firing repertoire of the neurons of the primate brain.

Differences in prostate and adipose tissue basic fibroblast growth factor: analysis of preliminary results.

OBJECTIVES: Basic fibroblast growth factor (bFGF or FGF-2) is mitogenic to human prostate epithelial and stromal cells, and it is reported to be elevated in the serum and urine of patients with various cancers, including prostate cancer. Obesity, with increased body fat, is a risk factor for prostate cancer through unknown mechanisms. Because adipose tissue is a source of FGF-2, we determined the quantity and quality of activity of FGF-2 in omental adipose tissue and compared it with normal and cancerous prostate tissues. METHODS: Using heparin-Sepharose chromatography, we extracted proteins from human omental adipose tissue, adenocarcinoma of the prostate, and benign prostatic hypertrophic (BPH) tissues. Each of the mitogenic proteins eluted with NaCl concentrations between 1.4 M and 1.8 M, similar to control FGF-2. Using FGF-2 antisera (which inhibited the mitogenic activity of the proteins), we performed Western blot analysis to confirm their homology to FGF-2. We also assessed recovery, mitogenicity, and angiogenicity of each of the proteins using thymidine incorporation into human umbilical vein endothelial cells and the chorioallantoic membrane assay. RESULTS: There was greater recovery of FGF-2 from omental adipose tissue compared with cancerous or BPH homogenates (40 micrograms [2.0 micrograms/g] versus 25 micrograms [1.25 micrograms/g] and 20 micrograms [1.0 microgram/g], respectively). Moreover. FGF-2 from adipose tissue had greater mitogenic activity (96.2% versus 74.8% and 54%; P < 0.05) and a greater angiogenic activity (5.1 vessels versus 2.9 and 1.8 vessels; P < 0.05) on the chorioallantoic assay. CONCLUSIONS: We suggest that human omental adipose tissue FGF-2 may demonstrate greater mitogenic and angiogenic activity than either BPH or prostate cancer tissue FGF-2. It is not known whether FGF-2 from adipose tissue qualitatively or quantitatively may underlie the relationship between obesity and prostate cancer.

Surgical treatment of obesity.

Surgical treatment of obesity by methods that have withstood over 5 years of clinical evaluation is effective in ameliorating and even curing manifest serious co-morbid diseases such as diabetes, hypertension, and respiratory distress in the majority of patients. Despite numerous shortcomings and limitations, surgical methods are the only viable alternative for achieving and maintaining substantial weight loss in dangerously obese patients and, therefore, represent a legitimate, often life-saving, intervention. Nevertheless, the magnitude of weight loss varies widely, as does the number of patients lost to follow-up or requiring multiple operations. Safety of performing the surgery and recognition and successful treatment of side effects in cooperating patients has improved greatly over the past 10 years. More effort needs to be put into improving patient selection to allocate patients to specific types of operations and to identify those patients who may not require surgery.

The gut and food intake: an update for surgeons.

Food intake is the simplest and most obvious measure of gastrointestinal function, yet it rarely receives more than cursory attention from surgeons. In this review we cover recent findings on relationships between gut function and appetite regulation mediated via neuropeptides influenced by afferent and efferent vagal activity. Evidence from the new discipline known as neurogastroenterology elucidates gastric and intestinal signals involved in the elicitation of hunger, satiety, and aversion. Discovery of the adipose-tissue-derived hormone, leptin, has energized the field of metabolism spawning increasing numbers of publications related to interactions between leptin and insulin release and glucose disposal, as well as appetitive behavior. Peptides such as cholecystokinin (CCK), the proglucagon-derived peptides, glucagon-like peptides 1 and 2 (GLP-1 and GLP-2), and the recently identified powerful intake-stimulating molecule, orexin, are examples of potential targets for drug development and studies of surgical pathophysiology. A major conclusion of this work is that the considerable redundancy and overlap between mediators of caloric intake subserving survival of the species, while beneficial after foregut surgery, contribute to the complexity of treating the global epidemic of obesity. Possibly knowledge derived from basic research in neurogastroenterology can translate into advances in surgical treatment of obesity.

Delivering drugs, via microdialysis, into the environment of extracellularly recorded hippocampal neurons in behaving primates.

Hippocampal neurons in primates have been extensively studied with electrophysiological and neuroanatomical methods. Much less effort has been devoted to examining these cells with contemporary pharmacological techniques. Therefore, we modified a recently developed integrative technique (N. Ludvig, P.E. Potter, S.E. Fox, Simultaneous single-cell recording and microdialysis within the same brain site in freely behaving rats: a novel neurobiological method, J. Neurosci. Methods 55 (1994) 31-40 [9] ) for cellular neuropharmacological studies in behaving monkeys. A driveable microelectrode-microdialysis probe guide assembly was implanted stereotaxically into the left hippocampus of squirrel monkeys (Saimiri sciureus) under isoflurane anesthesia. The assembly was covered with a protective cap. After 3 weeks of postsurgical recovery and behavioral training, the experimental subject was seated in a primate chair. For 4-5 h, single-cell recording and microdialysis were simultaneously performed in the hippocampal implantation site. The technique allowed the recording of both complex-spike cells and fast-firing neurons without the use of head restraint. The control microdialysis solution, artificial cerebrospinal fluid (ACSF), was replaced with either 1 M ethanol or 500 microM N-methyl-D-aspartate (NMDA) for 10-30 min intervals. The ethanol perfusions principally suppressed the firing of the neurons in the dialysis area. The NMDA perfusions initially increased the firing of local neurons, then caused electrical silence. These drug delivery/cell recording sessions were performed with 1-4 day intersession intervals over a 1-month period. The described method provides a tool to elaborate the pharmacology of primate hippocampal neurons during behavior and without the confounding effects of systemic drug administrations.