Obesity: Morley JE

Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, Thompson IM, Weidner W, Wu FC, Anonymous00084, Anonymous00085, Anonymous00086, Anonymous00087, Anonymous00088. · Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center, and Los Angeles BioMedical Research Institute, Torrance, CA 90509, USA. · J Androl. · Pubmed #18772485 No free full text.

This publication has no abstract.

Kalantar-Zadeh K, Horwich TB, Oreopoulos A, Kovesdy CP, Younessi H, Anker SD, Morley JE. · Harold Simmons Center for Kidney Disease Research and Epidemiology, Los Angeles Biomedical Research Center at Harbor-UCLA, Torrance, California 90509-2910, USA. · Curr Opin Clin Nutr Metab Care. · Pubmed #17563461 No free full text.

Abstract: PURPOSE OF REVIEW: Emerging data indicate that conventional cardiovascular risk factors (e.g. hypercholesterolemia and obesity) are paradoxically associated with better survival in distinct populations with wasting. We identify these populations and review survival paradoxes and common pathophysiologic mechanisms. RECENT FINDINGS: A 'reverse epidemiology' of cardiovascular risk is observed in chronic kidney disease, chronic heart failure, chronic obstructive lung disease, cancer, AIDS and rheumatoid arthritis, and in the elderly. These populations apparently have slowly progressive to full-blown wasting and significantly greater short-term mortality than the general population. The survival paradoxes may result from the time differential between the two competing risk factors [i.e. over-nutrition (long-term killer but short-term protective) versus undernutrition (short-term killer)]. Hemodynamic stability of obesity, protective adipokine profile, endotoxin-lipoprotein interaction, toxin sequestration of fat, antioxidation of muscle, reverse causation, and survival selection may also contribute. SUMMARY: The seemingly counterintuitive risk factor paradox is the hallmark of chronic disease states or conditions associated with wasting disease at the population level. Studying similarities among these populations may help reveal common pathophysiologic mechanisms of wasting disease, leading to a major shift in clinical medicine and public health beyond the conventional Framingham paradigm and to novel therapeutic approaches related to wasting and short-term mortality.

Banks WA, Farr SA, Morley JE. · GRECC, Veterans Affairs Medical Center-St. Louis and Saint Louis University School of Medicine, Division of Geriatrics, Department of Internal Medicine, USA. · Physiol Behav. · Pubmed #16781741 No free full text.

Abstract: Leptin is a pluripotent regulatory protein secreted by fat and exerts many effects through the CNS. Interpretation of the characteristics by which it crosses the blood-brain barrier (BBB) supports the view that leptin most potently signals the brain at serum levels well below those associated with the current definition of ideal body weight. This fits with the perspective that low serum levels of leptin are a signal to brain that a sufficient store of calories are available for the organism to expend energy for efforts unrelated to acquisition of calories. This would explain why low serum levels of leptin are permissive in many of the non-feeding actions of leptin, such as enhancing CNS-mediated immune function, memory, bone growth, reproduction, breathing, and neurogenesis. Triglycerides inhibit the transport of leptin across the BBB and so could be key in the onset of the peripheral leptin resistance, which is a hallmark of obesity. These results explain the paradox of why obesity should induce resistance to an anorectic: hypertriglyceridemia also occurs with starvation and we postulate that triglyceride-induced resistance to leptin transport across the BBB initially evolved to limit the signal of an anorectic to the brain during starvation.

Lee A, Patrick P, Wishart J, Horowitz M, Morley JE. · Department of Medicine, St Louis University Medical Center, and GRECC, St Louis VA Medical Center, St Louis, MO, USA. · Diabetes Obes Metab. · Pubmed #12190996 No free full text.

Abstract: BACKGROUND: Previous studies reported that administration of first generation alpha-glucosidase inhibitors (AGIs), such as voglibose or acarbose, produced exaggerated and sustained postprandial responses of glucagon-like peptide-1 (GLP-1), an incretin hormone from the enteroinsular axis, in healthy humans. Little is known about the postprandial release of GLP-1 after AGI therapy in diabetics. GLP-1 plays a role to mediate satiety. Any agent that substantially elevates GLP-1 levels may theoretically reduce hunger, increase satiation and limit food intake. OBJECTIVES: This study was performed to analyse the effect of miglitol, a more potent second generation AGI with fewer gastrointestinal side-effects, on the regulation of meal-related GLP-1 secretion and on the change of insulin-glucose dynamics as well as the release of gastric inhibitory polypeptide (GIP), another incretin hormone, after stimulation by an ordinary meal in obese type-2-diabetic subjects. Miglitol's subsequent influences on appetite sensations and food intake were also measured. DESIGN: In total, 8 obese type-2-diabetic women were randomized to receive treatment with 100 mg of miglitol or placebo three times a day for 2 days (six doses total) in a double-blind fashion. On day 3 of each treatment period (miglitol or placebo), measurements of GLP-1, GIP, insulin and glucose were taken periodically during 3 h after eating a 720 kcal breakfast. Appetite ratings with visual analogue scales (VASs) were used to assess ingestive behaviour hourly just before breakfast and hourly after for 6 h until immediately before lunch. The number of tuna sandwiches eaten at lunch was used to measure food consumption. RESULTS: The plasma GLP-1, glucose, insulin and GIP levels in response to the mixed meal were compared after the miglitol and placebo treatment. Miglitol effectively enhanced postprandial GLP-1 release and suppressed plasma GIP secretion. The ingestion of a mixed meal induced a remarkable rise in GLP-1 after miglitol as compared with placebo in overweight diabetic subjects. The meal-related rise in GLP-1 after miglitol was significantly greater at all time-points between 30 and 180 min than after the placebo. The postprandial incremental area under the curve for GLP-1 with miglitol treatment was about twofold that with the placebo. The GLP-1 level reached a maximum at 120 min after the mixed meal and steadily rose throughout the rest of the 3-h study period. In the miglitol-treated condition, the average caloric intake at lunch during a 30-min eating period was 12% lower (p < 0.05) as compared with that after the placebo in six out of the eight subjects who exhibited a GLP-1 rise after the breakfast meal by greater than 30% from the placebo-treated condition. Correspondingly, the average rating scores were significantly lower for hunger feelings and markedly greater for sensations of satiety under the miglitol treatment; beginning 2 and 3 h, respectively, before the lunch test. CONCLUSIONS: Miglitol induced an enhanced and prolonged GLP-1 release at high physiological concentrations after ingesting an ordinary meal in glycaemic-controlled diabetics. The excessive postprandial GLP-1 elevation after miglitol therapy modified feeding behaviour and food intake, and thereby has potential value in regulating appetite and stabilizing body weight in obese type-2-diabetic patients.

Perry HM, Morley JE, Miller DK. · No affiliation provided · Diabetes Care. · Pubmed #10480539 links to  free full text

This publication has no abstract.

Rolland Y, Lauwers-Cances V, Cristini C, Abellan van Kan G, Janssen I, Morley JE, Vellas B. · Service de Médecine Interne et de Gérontologie Clinique, Hôpital La Grave-Casselardit, Toulouse, France. · Am J Clin Nutr. · Pubmed #19369381 No free full text.

Abstract: BACKGROUND: In elders, decreased muscle mass (sarcopenia) and increased fat mass (obesity) may contribute to difficulties with physical function. OBJECTIVE: The objective was to examine the association of obesity, sarcopenia, and their combination (sarcopenic-obesity) with self-reported difficulties performing physical function in a cohort of community-dwelling elderly women. DESIGN: We assessed muscle and fat mass by dual-energy X-ray absorptiometry and self-reported difficulties with physical function in 1308 healthy women aged > or =75 y. Sarcopenia was defined as an appendicular skeletal muscle mass < or =2 SD below the mean in a young female reference group. Obesity was defined as a percentage body fat above the 60th percentile. Thirty-six sarcopenic-obese, 90 purely sarcopenic, 435 purely obese, and 747 women with a healthy body composition were studied. Anthropometric measures, health status, lifestyle habits, and self-reported difficulties with 6 different physical functions were obtained. RESULTS: Compared with women with a healthy body composition and after adjustment for confounders, purely sarcopenic women had no increased odds of having difficulties for all of the physical functions assessed, purely obese women had a 44-79% higher odds of having difficulties with most of the physical functions assessed (P < 0.05), and sarcopenic-obese women had a 2.60 higher odds of having difficulty climbing stairs and a 2.35 higher odds of having difficulty going down stairs (all P < 0.05). CONCLUSIONS: Sarcopenia is not associated with physical difficulties in the absence of obesity. However, in the presence of obesity, sarcopenia tends to add difficulty for some physical functions.

Chu LW, Tam S, Kung AW, Lo S, Fan S, Wong RL, Morley JE, Lam KS. · Division of Geriatric Medicine, Faculty of Medicine, Research Center of Heart, Brain, Hormone and Healthy Aging, University of Hong Kong, Hong Kong SAR. · J Am Geriatr Soc. · Pubmed #18482300 No free full text.

Abstract: OBJECTIVES: To investigate the effects of the changes in serum bioavailable and total testosterone (TT) levels with aging on visceral body fat distribution and muscle strength in Chinese men. DESIGN: Cross-sectional study. SETTING: Ambulatory care. PARTICIPANTS: Four hundred seventy-five healthy ambulatory Chinese men (aged 18-89, body mass index (BMI) 16.4-40.0 kg/m(2)). MEASUREMENTS: Morning serum total and bioavailable testosterone levels, waist circumference (WC), waist-hip ratio (WHR), and right handgrip strength. RESULTS: Mean serum TT levels fell mildly but significantly with aging (P=.02, linear trend; one-way analysis of variance (ANOVA)), whereas mean serum bioavailable testosterone (BT) levels fell greatly with aging (P<.001, linear trend, one-way ANOVA). The rates of decline in serum TT and BT levels were 0.2% and 1.14% per year, respectively. [Correction added after online publication 14-May-2008: BT levels have been corrected from 1.44% to 1.14%.] After adjustment for adiposity according to BMI, multiple linear regression analyses showed that age remained significantly related to serum TT and BT levels. Handgrip strength decreased with age (correlation coefficient (r)=-0.394, P<.001) and was greater with higher serum BT levels (r=0.239, P<.001) but not with higher TT levels. WHR, before and after adjustment for BMI, was inversely related to serum TT (r=-0.34 and -0.197 respectively, P<.001) and BT levels (r=-0.104, P<.05 and -0.161, P<.001, respectively). CONCLUSION: In Chinese men, serum BT levels decreased with aging and may contribute to central obesity and poorer muscle strength in aging men.

Farr SA, Yamada KA, Butterfield DA, Abdul HM, Xu L, Miller NE, Banks WA, Morley JE. · Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA. · Endocrinology. · Pubmed #18276751 links to  free full text

Abstract: Obesity is associated with cognitive impairments. Long-term mechanisms for this association include consequences of hyperglycemia, dyslipidemia, or other factors comprising metabolic syndrome X. We found that hypertriglyceridemia, the main dyslipidemia of metabolic syndrome X, is in part responsible for the leptin resistance seen in obesity. Here we determined whether triglycerides have an immediate and direct effect on cognition. Obese mice showed impaired acquisition in three different cognitive paradigms: the active avoidance T-maze, the Morris water maze, and a food reward lever press. These impairments were not attributable to differences in foot shock sensitivity, swim speed, swimming distance, or voluntary milk consumption. Impaired cognition in obese mice was improved by selectively lowering triglycerides with gemfibrozil. Injection into the brain of the triglyceride triolein, but not of the free fatty acid palmitate, impaired acquisition in normal body weight mice. Triolein or milk (97% of fats are triglycerides), but not skim milk (no triglycerides), impaired maintenance of the N-methyl-d-aspartate component of the hippocampal long-term synaptic potential. Measures of oxidative stress in whole brain were reduced by gemfibrozil. We conclude that triglycerides mediate cognitive impairment as seen in obesity, possibly by impairing maintenance of the N-methyl-d-aspartate component of hippocampal long-term potentiation, and that lowering triglycerides can reverse the cognitive impairment and improve oxidative stress in the brain.

Baumgartner RN, Wayne SJ, Waters DL, Janssen I, Gallagher D, Morley JE. · Aging and Genetic Epidemiology Program, Division of Epidemiology and Preventive Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131,USA. · Obes Res. · Pubmed #15687401 No free full text.

Abstract: OBJECTIVE: To determine the association of sarcopenic obesity with the onset of Instrumental Activities of Daily Living (IADL) disability in a cohort of 451 elderly men and women followed for up to 8 years. RESEARCH METHODS AND PROCEDURES: Sarcopenic obesity was defined at study baseline as appendicular skeletal muscle mass divided by stature squared <7.26 kg/m2 in men and 5.45 kg/m2 in women and percentage body fat greater than the 60th percentile of the study sample (28% body fat in men and 40% in women). Incident disability was defined as a loss of two or more points from baseline score on the IADL. Subjects with disability at baseline (scores < 8) were excluded. Cox proportional hazards analysis was used to determine the association of baseline sarcopenic obesity with onset of IADL disability, controlling for potential confounders. RESULTS: Subjects with sarcopenic obesity at baseline were two to three times more likely to report onset of IADL disability during follow-up than lean sarcopenic or nonsarcopenic obese subjects and those with normal body composition. The relative risk for incident disability in sarcopenic obese subjects was 2.63 (95% confidence interval, 1.19 to 5.85), adjusting for age, sex, physical activity level, length of follow-up, and prevalent morbidity. DISCUSSION: This is the first study, to our knowledge, to indicate that sarcopenic obesity is independently associated with and precedes the onset of IADL disability in the community-dwelling elderly. The etiology of sarcopenic obesity is unknown but may include a combination of decreases in anabolic signals and obesity-associated increases in catabolic signals in old age.

Banks WA, Coon AB, Robinson SM, Moinuddin A, Shultz JM, Nakaoke R, Morley JE. · Department of Internal Medicine, Division of Geriatrics, Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, St. Louis University School of Medicine, 915 N. Grand Boulevard, St. Louis, MO 631056, USA. · Diabetes. · Pubmed #15111494 links to  free full text

Abstract: Obesity is associated with leptin resistance as evidenced by hyperleptinemia. Resistance arises from impaired leptin transport across the blood-brain barrier (BBB), defects in leptin receptor signaling, and blockades in downstream neuronal circuitries. The mediator of this resistance is unknown. Here, we show that milk, for which fats are 98% triglycerides, immediately inhibited leptin transport as assessed with in vivo, in vitro, and in situ models of the BBB. Fat-free milk and intralipid, a source of vegetable triglycerides, were without effect. Both starvation and diet-induced obesity elevated triglycerides and decreased the transport of leptin across the BBB, whereas short-term fasting decreased triglycerides and increased transport. Three of four triglycerides tested intravenously inhibited transport of leptin across the BBB, but their free fatty acid constituents were without effect. Treatment with gemfibrozil, a drug that specifically reduces triglyceride levels, reversed both hypertriglyceridemia and impaired leptin transport. We conclude that triglycerides are an important cause of leptin resistance as mediated by impaired transport across the BBB and suggest that triglyceride-mediated leptin resistance may have evolved as an anti-anorectic mechanism during starvation. Decreasing triglycerides may potentiate the anorectic effect of leptin by enhancing leptin transport across the BBB.

Wittert GA, Turnbull H, Hope P, Morley JE, Horowitz M. · Department of Medicine, Royal Adelaide Hospital, Adelaide SA 5000, Australia. · Am J Physiol Regul Integr Comp Physiol. · Pubmed #15003944 No free full text.

Abstract: The aims of this study were to determine in the marsupial Sminthopsis crassicaudata, the effects of leptin on food intake, body weight, tail width (a reflection of fat stores), and leptin mRNA, after caloric restriction followed by refeeding ad libitum with either a standard or high-fat preferred diet. S. crassicaudata (n = 32), were fed standard laboratory diet (LabD; 1.01 kcal/g, 20% fat) ad libitum fo 3 days. On days 4-10, animals received LabD at 75% of basal intake and then (days 11-25) were fed either LabD or a choice of LabD and mealworms (MW; 2.99 kcal/g, 30% fat); during this time, half the animals (n = 8) in each group received either leptin (2.5 mg/kg) or PBS intraperitoneally two times daily. On day 26, animals were killed and fat was removed for assay of leptin mRNA. At baseline, body weight, tail width, and food intake were similar in each group. After caloric restriction, body weight (P < 0.001) and tail width (P < 0.001) decreased. On return to ad libitum feeding in the PBS-treated animals, body weight and tail width returned to baseline in the LabD-fed animals (P < 0.001) and increased above baseline in the MW-fed animals (P < 0.001). In the LabD groups, tail width (P < 0.001) and body weight (P < 0.001) decreased after leptin compared with PBS. In the MW groups, the increase in tail width (P < 0.001) and body weight (P = 0.001) were attenuated after leptin compared with PBS. The expression of leptin mRNA in groups fed MW were greater in PBS than in leptin-treated animals (P < 0.05). Therefore, after diet-induced weight loss, leptin prevents a gain in fat mass in S. crassicaudata; this has potential implications for the therapeutic use of leptin.

Lindeman RD, Yau CL, Baumgartner RN, Morley JE, Garry PJ, Anonymous00379. · Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque 87131, USA. · J Nutr Health Aging. · Pubmed #12766795 No free full text.

Abstract: BACKGROUND: The American Diabetes Association s Expert Committee on the Diagnosis and Classification of Diabetes Mellitus has made the recommendation that all individuals over the age of 45 years should be screened for diabetes every 3 years. OBJECTIVE: This study was designed to determine the necessity for screening healthy elderly (> 65 years) this frequently using fasting serum glucose (FSG) determinations. DESIGN: This is a longitudinal study of initially healthy, upper middle class, community-based volunteers, mostly age 65 years and older at entry into the study. Participants were followed longitudinally with annual FSG concentrations and body mass indices (BMI) for periods up to 18 years (mean 12.4 years). RESULTS: Only 4 of 299 individuals with entry FSG < 126 mg/dl (mean + S.D. age at entry 71.6 + 4.8 years) and 6 or more annual visits have subsequently met the Expert Committee criteria for the diagnosis of diabetes (two consecutive FSGs > 126 mg/dl unless under treatment). When one examines the slopes of FSGs plotted over time (years) for each individual, more participants had a negative slope (220) than positive slope (79), i.e., their FSGs tended to decrease with age. None of the 68 individuals entered age > 75 years subsequently developed diabetes or a significantly positive slope. CONCLUSIONS: It does not appear necessary to screen non-obese elders (excluding minorities) age >65 years with a FSG < 100 mg/dl, or those age >75 years every 3 years as recommended.

Banks WA, Altmann J, Sapolsky RM, Phillips-Conroy JE, Morley JE. · Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center-St. Louis, St. Louis, Missouri 63106, USA. · J Clin Endocrinol Metab. · Pubmed #12629112 links to  free full text

Abstract: We measured serum leptin levels in two groupings of wild male baboons, one with access to abundant quantities of food from gardens and garbage dumps near human habitations (Garbage; n = 11) and one without access (No Garbage; n = 10). A Garbage subgroup had high leptin levels (Garbage HL), whereas the rest of the Garbage group had low leptin levels (Garbage LL) similar to those in the No Garbage group. The Garbage HL individuals were obese, with higher mass, body mass index, and leptin to mass ratios; were insulin to resistant, with elevations in serum insulin, glucose, and insulin to glucose ratios; and were hyperlipidemic. This syndrome X-like condition occurred only in the Garbage HL subset. The Garbage LL subset did not differ from the No Garbage individuals in mass, body mass index, leptin to mass ratio, insulin, glucose, or insulin to glucose ratios. The highest cholesterol levels, however, occurred in the Garbage LL individuals, suggesting that susceptibility to hyperlipidemia is distinguishable from susceptibility to obesity and insulin resistance. The differences were not explained by age or social status. These results show that a subgroup of wild baboons is susceptible to developing obesity and insulin resistance and that this susceptibility is not related to age or social rank.

Rodríguez-Saldaña J, Morley JE, Reynoso MT, Medina CA, Salazar P, Cruz E, Torres AL. · Department of Public Health and AFINES Program, School of Medicine, U.N.A.M. Pacific Operating Center, México City, México. · J Am Geriatr Soc. · Pubmed #12028255 No free full text.

Abstract: OBJECTIVES: To examine the prevalence and effects of diabetes mellitus in a subgroup of older Mexicans to allow comparisons to older persons of Mexican origin living in the United States. DESIGN: Longitudinal study. SETTING: High-rise retirement housing in Mexico City. PARTICIPANTS: Seven hundred eighty-five public servants and their family members aged 65 and older. MEASUREMENTS: Geriatric survey of function; mental status and depression; a physical examination; and blood samples for glucose and cholesterol. RESULTS: The prevalence of diabetes mellitus in this population was 15.1%, substantially lower than the prevalence reported in people of Mexican origin living in the United States. Nondiabetics were more obese than diabetics. Diabetes mellitus was more common in men than women. The mortality rate was greater in diabetics than nondiabetics (relative risk=1.73, P <.05). Diabetics had more coronary artery disease and were more likely to die from myocardial infarction and neoplasms than nondiabetics. Diabetics were more likely to be functionally impaired (P <.0001) but no more likely to fall or to have fractures. Diabetics did not differ from nondiabetics in cognitive impairment or level of dysphoria. CONCLUSION: These studies highlight some important similarities and differences in comparing a middle class subgroup of older diabetics in Mexico City with diabetics of Mexican origin living in the United States.

Kumar VB, Bernardo AE, Vyas K, Franko M, Farr S, Lakshmanan L, Buddhiraju C, Morley JE. · Geriatric Research, Education and Clinical Center, VA Medical Center, St. Louis, MO 63125, USA. · Life Sci. · Pubmed #11720083 No free full text.

Abstract: Genetically obese (ob/ob) mice were employed for the study of the effect of metformin on activity and expression of nitric oxide synthase (NOS ) in vitro and in vivo. For in vitro analysis, mouse liver extracts were used. For the in vivo study, (ob/ob) and their control litter mates (ob/c) mice were injected with specified amounts of metformin and the expression of NOS in the adipose tissue and hypothalamus was measured by Western blotting. Results show that metformin exhibited a biphasic effect on NOS activity in vitro. Expression of metformin was differentially altered in the hypothalamus and adipose tissues of the normal and ob/ob animals that were treated with metformin. Further, a significant decrease in food intake occurred in the (ob/ob) mice that received metformin. This decrease in food intake was not accompanied by changes in serum glucose. At inhibitory concentrations, hypothalamic NOS expression changes differentially in normal and ob/ob mice. In normal mice, metformin stimulated NOS expression, while in ob/ob mice there was an inhibition. NOS expression increased in brown adipose tissue of metformin treated control mice, while no such increase was observed in ob/ob mice. No effect of metformin was observed in white adipose tissue of control or obese mice. Thus, metformin may produce anorectic effects through modulation of NOS.

Ng KL, Vozzo R, Hope PJ, Chapman IM, Morley JE, Horowitz M, Wittert GA. · Department of Medicine, Royal Adelaide Hospital, Australia. · Physiol Behav. · Pubmed #10222485 No free full text.

Abstract: The role of dietary fat, as opposed to total energy intake, in the etiology of obesity is controversial. The aim of this study was to determine the effect of macronutrient content, specifically changes in dietary fat on body weight, fat stores, and food intake in S. crassicaudata, a marsupial that stores about 25% of total body fat in its tail. Female animals were divided into three groups (n = 7-9) matched for food intake per gram of body weight. Each group of animals was fed, ad lib an isocaloric diet (1.01 kcal/g), which contained either 10, 20, or 40% of calories from fat. Body weight, food intake, and tail width (an index of body fat stores) were measured daily. Over 21 days, cumulative energy intake was less (p = 0.026) in the 40% fat group compared to the 10% fat group. Despite the differences in food intake, body weight in each group remained stable throughout the study, so that at day 21 there were no differences in the body weights between the three groups. In contrast, tail width increased in the animals who received the 40% fat diet compared to either the 10% (p = 0.016) or 20% (p = 0.001) fat intake groups, whereas there was no significant change in tail width in either of these two groups. These observations indicate that macronutrient composition has a role, independent of total calories in the regulation of food intake and body fat stores, specifically that dietary fat promotes adiposity, independent of total caloric intake.