Circulating TNF alpha receptor levels identify older adults who fail to regain weight after acute weight loss.

OBJECTIVE: Some healthy older adults have difficulty regaining weight after acute weight loss, and the reason for this failure to regain weight is unknown. The objective of this study was to determine if elevated leptin or pro-inflammatory cytokine levels are associated with failure to regain weight over two years after an acute weight loss intervention. DESIGN: Two year prospective study after an acute weight loss intervention. SETTING: University of Washington Medical Center from 2001-2006. PARTICIPANTS: Nineteen older (≥ 70 years old) men and women. MEASUREMENTS: Body weights, health status questionnaire, body composition data, serum leptin, glucose, insulin, C- reactive protein and pro-inflammatory cytokine levels were measured every six months for two years. RESULTS: Five subjects out of 19 failed to regain weight after two years. The subjects who failed to regain weight after 2 years had higher circulating levels of tumor necrosis factor receptor particle 55 (TNFRp55) at baseline and at 6, 12, 18 and 24 months of follow up compared to subjects who regained weight after 2 years (P = 0.02 ). CONCLUSION: Five out of 19 older subjects had difficulty regaining weight for up to 2 years following an acute weight loss intervention, and their TNFRp55 levels were persistently higher than in subjects who regained weight. Greater TNF α action, as reflected by higher circulating levels of TNFRp55, could be contributing towards inability of some older persons to regain weight after acute weight loss.

Leptin levels recover normally in healthy older adults after acute diet-induced weight loss.

OBJECTIVES: Involuntary weight loss affects 20% of community dwelling older adults. The underlying mechanism for this disorder is unknown. Objective is to determine if failure of older persons to regain weight is associated with elevated pro-inflammatory cytokine and leptin levels. DESIGN: Prospective diet intervention study. SETTING: University of Washington Medical Center from 2001-2005. PARTICIPANTS: Twenty-one younger (18-35 years old) and nineteen older (>or= 70 years old) men and women. INTERVENTION: Each subject was placed for two weeks on a weight-maintaining diet, followed in sequence by 2 weeks of 30% caloric restriction, then 4 weeks of ad libitum food intake. MEASUREMENTS: Plasma leptin levels, fasting serum pro-inflammatory cytokine levels, and peripheral blood mononuclear cell cytokine levels were measured. RESULTS: Leptin levels in the two cohorts decreased after caloric restriction and increased after ad-libitum food consumption resumed. Plasma TNF alpha levels were higher in older subjects compared to younger adults. However, there was no association between changes in TNF alpha levels and changes in AUC leptin. CONCLUSION: Leptin levels in healthy older individuals responded appropriately in a compensatory manner to changes in body weight. These data do not support a cytokine dependent elevation in leptin levels as being responsible for the failure of older adults to regain weight.

Sleep, ghrelin, leptin and changes in body weight during a 1-year moderate-intensity physical activity intervention.

OBJECTIVE: To investigate cross-sectional and longitudinal relationships among exercise, sleep, ghrelin and leptin. METHODS: We randomly assigned 173 post-menopausal sedentary overweight (body mass index >or=24.0 kg/m(2) and >33% body fat) women aged 50-75 years living in western Washington State to either a facility- and home-based moderate-intensity physical activity intervention or a stretching control group. Fasting plasma ghrelin, leptin, measured height, weight and self-reported sleep were assessed at baseline and 12 months. RESULTS: There were no consistent cross-sectional patterns between self-reported sleep measures and ghrelin or leptin at baseline. The weight loss differences between exercisers and stretchers were greater for those who slept less at follow-up than at baseline compared to those whose sleep duration did not change (-3.2 kg, 95% confidence interval (CI) -5.8, -0.5). Improvements in sleep quality were associated with significantly greater differences between exercisers and stretchers for ghrelin increases (improved vs same sleep quality: +115 pg/ml, 95% CI +25, +206) and leptin decreases (improved vs worsened sleep quality: -5.7 ng/ml, 95% CI -9.5, -1.5). CONCLUSION: There was only limited evidence that changes in sleep duration or quality modified exercise-induced changes in weight, ghrelin or leptin. Moreover, the observed differences were not in the directions hypothesized. Future longitudinal studies including population-based samples using objective measures of sleep and long follow-up may help to clarify these relationships.

Changes in 24-h area-under-the-curve ghrelin values following diet-induced weight loss are associated with loss of fat-free mass, but not with changes in fat mass, insulin levels or insulin sensitivity.

OBJECTIVE: To determine which parameters of body composition or metabolism best correlate with changes in 24 h ghrelin levels following weight loss. DESIGN: A 3-month low-calorie diet followed by 3 months of weight stabilization. SUBJECTS: Twelve overweight and obese adult men and women. MEASUREMENTS: Body composition by underwater weighing, abdominal fat depots, leptin, ghrelin and parameters of insulin and lipid metabolism. RESULTS: Increased 24 h ghrelin levels after weight loss correlated with decreases in body mass index, subcutaneous fat and fat-free mass (FFM), but not with changes in fat mass, fat cell size, leptin, insulin, insulin sensitivity, lipids or free fatty acid levels. The change in FFM correlated with the rise in ghrelin levels independently of body adiposity. DISCUSSION: Alterations in FFM with diet-induced weight loss may play a role in ghrelin regulation. Changes in ghrelin levels could, then, serve as an integrative signal reflecting changes in FFM to hypothalamic centers controlling energy homeostasis.

A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans.

The recently discovered orexigenic peptide ghrelin is produced primarily by the stomach and circulates in blood at levels that increase during prolonged fasting in rats. When administered to rodents at supraphysiological doses, ghrelin activates hypothalamic neuropeptide Y/agouti gene-related protein neurons and increases food intake and body weight. These findings suggest that ghrelin may participate in meal initiation. As a first step to investigate this hypothesis, we sought to determine whether circulating ghrelin levels are elevated before the consumption of individual meals in humans. Ghrelin, insulin, and leptin were measured by radioimmunoassay in plasma samples drawn 38 times throughout a 24-h period in 10 healthy subjects provided meals on a fixed schedule. Plasma ghrelin levels increased nearly twofold immediately before each meal and fell to trough levels within 1 h after eating, a pattern reciprocal to that of insulin. Intermeal ghrelin levels displayed a diurnal rhythm that was exactly in phase with that of leptin, with both hormones rising throughout the day to a zenith at 0100, then falling overnight to a nadir at 0900. Ghrelin levels sampled during the troughs before and after breakfast correlated strongly with 24-h integrated area under the curve values (r = 0.873 and 0.954, respectively), suggesting that these convenient, single measurements might serve as surrogates for 24-h profiles to estimate overall ghrelin levels. Circulating ghrelin also correlated positively with age (r = 0.701). The clear preprandial rise and postprandial fall in plasma ghrelin levels support the hypothesis that ghrelin plays a physiological role in meal initiation in humans.

Defective dietary induction of uncoupling protein 3 in skeletal muscle of obesity-prone rats.

OBJECTIVE: The goal of this study was to determine whether differential induction of skeletal muscle uncoupling protein 3 (UCP3) contributes to the development of diet-induced obesity (DIO) or resistance to the development of obesity (DR) when rats are placed on a moderate fat (31%) high energy (HE) diet. RESEARCH METHODS AND PROCEDURES: Gastrocnemius muscle was obtained from Sprague-Dawley rats that were identified as DIO-prone (n = 5) or DR (n = 5) on the basis of urinary norepinephrine excretion while consuming a chow diet. Muscle was also obtained from animals in the top tertile of weight gain (DIOHE, n = 5) and the bottom tertile of weight gain (DRHE, n = 5) after 2 weeks on the HE diet. UCP3 and actin mRNA levels were measured in all muscle samples by Northern analysis. To distinguish the effect of dietary energy content from the effect of obesity itself, we studied additional DIO and DR animals that had been returned to a chow diet for 10 weeks after consuming a HE diet for 10 weeks. RESULTS: The muscle UCP3/actin mRNA ratio in animals that resisted the development of obesity during 2 weeks on the HE diet was 3-fold higher than in the other groups (DRHE = 3.24 +/- 0.83, DIOHE = 0.91 +/- 0.20, DIO-prone = 0.72 +/- 0.15, DR = 0.63 +/- 0.15; p = 0.002). However, there was no difference in muscle UCP3/actin mRNA ratios between DIO animals and DR animals that had been fed the HE diet for 10 weeks and then returned to either an ad libitum chow diet for 10 weeks (DIO = 13.8 +/- 3.53, DR = 11.1 +/- 3.43, p = NS) or to a restricted chow diet for 10 weeks (DIO = 11.0 +/- 2.85, DR = 10.6 +/- 2.20, p = NS) despite significantly greater body weight of the DIO animals. DISCUSSION: DR animals may initially resist weight gain when placed on a HE diet through a greater induction of muscle UCP3. This induction is transient and is related more closely to dietary fat content than to body fat stores. DIO animals show no initial induction of muscle UCP3, which may contribute to their increased metabolic efficiency soon after exposure to a HE diet.

Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats.

Hypothalamic melanocortins are among several neuropeptides strongly implicated in the control of food intake. Agonists for melanocortin 4 (MC-4) receptors such as alpha-melanocyte-stimulating hormone (alpha-MSH), a product of proopiomelanocortin (POMC), reduce food intake, whereas hypothalamic agouti-related protein (AgRP) is a MC-4 receptor antagonist that increases food intake. To investigate whether reduced melanocortin signaling contributes to hyperphagia induced by uncontrolled diabetes, male Sprague-Dawley rats were studied 7 days after administration of streptozotocin (STZ) or vehicle. In addition, we wished to determine the effect of diabetes on muscle uncoupling protein 3 (UCP-3), a potential regulator of muscle energy metabolism. STZ diabetic rats were markedly hyperglycemic (31.3 +/- 1.0 mmol/l; P < 0.005) compared with nondiabetic controls (9.3 +/- 0.2 mmol/l). Insulin treatment partially corrected the hyperglycemia (18.8 +/- 2.5 mol/l; P < 0.005). Plasma leptin was markedly reduced in STZ diabetic rats (0.4 +/- 0.1 ng/ml; P < 0.005) compared with controls (3.0 +/- 0.4 ng/ml), an effect that was also partially reversed by insulin treatment (1.8 +/- 0.3 ng/ml). Untreated diabetic rats were hyperphagic, consuming 40% more food (48 +/- 1 g/day; P < 0.005) than controls (34 +/- 1 g/day). Hyperphagia was prevented by insulin treatment (32 +/- 2 g/day). In untreated diabetic rats, hypothalamic POMC mRNA expression (measured by in situ hybridization) was reduced by 80% (P < 0.005), whereas AgRP mRNA levels were increased by 60% (P < 0.01), suggesting a marked decrease of hypothalamic melanocortin signaling. The change in POMC, but not in AgRP, mRNA levels was partially reversed by insulin treatment. By comparison, the effects of diabetes to increase hypothalamic neuropeptide Y (NPY) expression and to decrease corticotropin-releasing hormone (CRH) expression were normalized by insulin treatment, whereas the expression of mRNA encoding the long form of the leptin receptor in the arcuate nucleus was unaltered by diabetes or insulin treatment. UCP-3 mRNA expression in gastrocnemius muscle from diabetic rats was increased fourfold (P < 0.005), and the increase was prevented by insulin treatment. The effect of uncontrolled diabetes to decrease POMC, while increasing AgRP gene expression, suggests that reduced hypothalamic melanocortin signaling, along with increased NPY and decreased CRH signaling, could contribute to diabetic hyperphagia. These responses, in concert with increased muscle UCP-3 expression, may also contribute to the catabolic effects of uncontrolled diabetes on fuel metabolism in peripheral tissues.

Association between baseline plasma leptin levels and subsequent development of diabetes in Japanese Americans.

OBJECTIVE: Plasma leptin levels correlate strongly with increased total adipose tissue, a known risk factor for type 2 diabetes, yet the role of leptin in the etiology of diabetes remains unclear. We sought to determine whether leptin is a risk factor for development of diabetes in Japanese Americans. RESEARCH DESIGN AND METHODS: We compared baseline leptin levels in 370 nondiabetic Japanese Americans who remained nondiabetic for 5-6 years of follow-up with those of 40 nondiabetic Japanese Americans who developed diabetes during follow-up. All participants had computed tomography measurements of baseline subcutaneous chest, abdomen, thigh, and intra-abdominal fat, with total fat defined as the sum of all these measurements. RESULTS: The mean age was 51.7 +/- 11.7 years for men and 51.9 +/- 12.0 years for women. The 23 men who developed diabetes had significantly higher leptin levels than the 212 men who remained nondiabetic (P < 0.01). Among men, baseline leptin levels predicted diabetes risk independent of baseline total fat, insulin, insulin resistance, glucose, or age in separate multiple logistic regression models (relative risk adjusted for baseline total fat = 1.80 per SD increase [2.7 ng/ml], 95% CI 1.02-3.17). This association was particularly strong among men in the top decile for intra-abdominal fat. In contrast, the 17 women who developed diabetes had leptin levels similar to those of the 158 women who remained nondiabetic (P = 0.31). CONCLUSIONS: Among Japanese Americans, increased baseline leptin levels are associated with increased risk of developing diabetes in men but not in women.

Leptin does not fully account for the satiety activity of adipose tissue-conditioned medium.

To determine whether leptin alone accounts for the satiety activity secreted by native adipose tissue, we prepared culture media conditioned by microdissected adipose tissue from overfed Long-Evans rats, fa/fa rats, or db/db mice (media A, B, and C, respectively). Medium A significantly suppressed food intake following intracerebroventricular delivery to Long-Evans rats (2-h chow intake = 68 +/- 5% of baseline, P < 0.001). Media B and C significantly suppressed food intake following intraperitoneal delivery to ob/ob mice (24-h chow intake = 56 +/- 7% of baseline for medium B, P = 0. 001; 4-day chow intake = 78 +/- 3% of baseline for medium C, P = 0. 004). Using a leptin receptor-based bioassay, we determined that the leptin concentration of medium C was 392 +/- 18 ng/ml. This concentration was 20-fold lower than the concentration of recombinant murine leptin required to produce a similar degree of feeding suppression following 5 days of administration to ob/ob mice. Neither medium conditioned by adipose tissue from ob/ob mice nor medium conditioned by adipose tissue from fa/fa rats and subsequently immunodepleted of leptin had significant satiety activity. We conclude that leptin is necessary but not sufficient to account for the satiety activity of native adipose tissue, perhaps due to the production by adipocytes of a cofactor that augments the ability of leptin to suppress feeding.