Reduction In Plasma Leptin Levels Research Articles

Partial Leptin Reduction as an Insulin Sensitization and Weight Loss Strategy

The physiological role of leptin is thought to be a driving force to reduce food intake and increase energy expenditure. However, leptin therapies in the clinic have failed to effectively treat obesity, predominantly due to a phenomenon referred to as leptin resistance. The mechanisms linking obesity and the associated leptin resistance remain largely unclear. With various mouse models and a leptin neutralizing antibody, we demonstrated that hyperleptinemia is a driving force for metabolic disorders. A partial reduction of plasma leptin levels in the context of obesity restores hypothalamic leptin sensitivity and effectively reduces weight gain and enhances insulin sensitivity. These results highlight that a partial reduction in plasma leptin levels leads to improved leptin sensitivity, while pointing to a new avenue for therapeutic interventions in the treatment of obesity and its associated comorbidities.

The Influence of a Meal Replacement Formula on Leptin Regulation in Obese Adults

Background and Purpose: The increasing prevalence of overweight and obese adults warrants improved dietary strategies for weight management and metabolic control. Hence, the objective of this study was to investigate the effects of a high-protein diet on leptin regulation. Methods: This study was a secondary analysis of data collected from a randomized controlled trial, conducted in 90 overweight adults (age: 47.5 ± 7.5 yrs.; BMI: 31.5 ± 2.3 kg/m2) who were followed over a 24-week control period. Changes in leptin levels were quantified to determine the influence of age, gender, leptin baseline levels, weight loss and intervention type. Participants were randomized into 3 interventions groups: 1) therapeutic lifestyle changes, (LS); 2) standardized meal replacement (Almased®) (MR); and 3) standardized meal replacement accompanied by supervised physical training (MRPT). For the analyses, both diet groups (MR, MRPT) were pooled into one common group and compared to the LS group in a parallel two-group study design with endpoint assessment after 24 weeks of intervention. Results: In total, 83 participants completed the 24-week study. Significant improvements in body composition and metabolic regulation occurred in all intervention participants regardless of their group assignment (LS; MR, MRPT). Participants’ consumption of the meal replacement (MR; MRPT) had an independent, significant effect on serum leptin levels (-15.5 ± 7.5 and -12.5 ± 7.8 vs. -8.7 ± 6.1 ng/ml). Greater body weight reductions were also observed in the diet groups (-8.9 ± 3.9 kg) compared to the LS group (-6.2 ± 4.2 kg). Conclusions: Our findings suggest that meal replacement can safely and effectively produce significant weight loss, which may be in part due to a reduction in plasma leptin levels. ClinicalTrials.gov Identifier: NCT00356785

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Long-term sympathoinhibitory effects of surgically induced weight loss in severe obese patients.

Weight loss improves insulin sensitivity and exerts sympathomodulatory effects. No data, however, are available on the effects of the weight loss induced by vertical sleeve gastrectomy on sympathetic neural drive, insulin sensitivity, and their reciprocal cross talks. In 10 severe obese hypertensives (age, 54.0±2.3 years [mean±SEM]), we measured sphygmomanometric blood pressure, heart rate, body mass index, homeostatic model assessment index, plasma leptin, muscle sympathetic nerve traffic (microneurography), and baroreflex sensitivity (vasoactive drug technique). Measurements were performed 2 to 3 days before surgery and repeated 6 and 12 months after the procedure. Ten matched hypertensive obeses not undergoing gastrectomy served as controls. Six months after bariatric surgery, a significant (P<0.05) reduction in body mass index (-9.1±1.4 kg/m(2)), sphygmomanometric systolic blood pressure (-10.2±4.5 mm Hg), heart rate (-11.0±2.4 bpm), homeostatic model assessment index (-3-3±1.3 AU), plasma leptin (-53.6±8.8 μg/L), and muscle sympathetic nerve traffic (-15.0±3.4 bursts/100 heart beats) was observed. The weight loss, the plasma leptin reduction, and the sympathetic inhibition were maintained after 12 months, whereas homeostatic model assessment index showed a tendency to return toward presurgery values. A significant improvement in baroreflex control of sympathetic nerve traffic was observed both 6 (+32.1%; P<0.05) and 12 months (+60.7%; P<0.01) after gastrectomy. No significant changes in the above-mentioned variables were detected in the control group. These data provide evidence that massive weight loss induced by sleeve gastrectomy triggers profound sympathoinhibitory effects, associated with a stable and significant reduction in plasma leptin levels, whereas the improvement in insulin sensitivity was attenuated with time and unrelated to the sympathoinhibition.

Diurnal Intermittent Fasting during Ramadan: The Effects on Leptin and Ghrelin Levels

We aimed to assess the effect of Islamic intermittent fasting, during and outside of Ramadan, on plasma levels of leptin and ghrelin while controlling for several potential confounding variables. Eight healthy male volunteers with a mean age of 26.6±4.9 years reported to the sleep disorders center (SDC) at King Saud University on four occasions: 1) adaptation; 2) 4 weeks before Ramadan while performing Islamic fasting for 1 week (baseline fasting) (BLF); 3) 1 week before Ramadan (non-fasting baseline) (BL); and 4) during the second week of Ramadan while fasting. Plasma leptin and ghrelin levels were measured using enzyme-linked immunoassays at 22:00, 02:00, 04:00, 06:00, and 11:00. During BLF, there were significant reductions in plasma leptin concentrations at 22:00 and 02:00 compared with the baseline concentrations (at 22:00: 194.2±177.2 vs. 146.7±174.5; at 02:00: 203.8±189.5 vs. 168.1±178.1; p<0.05). During Ramadan, there was a significant reduction in plasma leptin levels at 22:00 (194.2±177.2 vs. 132.6±130.4, p<0.05). No significant difference in plasma ghrelin concentrations was detected during the BL, BLF, or Ramadan periods. Cosinor analyses of leptin and ghrelin plasma levels revealed no significant changes in the acrophases of the hormones during the three periods. The nocturnal reduction in plasma leptin levels during fasting may be the result of the changes in meal times during fasting.

Leptin as a mediator between obesity and cardiac dysfunction

Obesity is now recognised as one of the most important risk factors for heart disease. Obese individuals have high circulating levels of leptin, a hormone secreted by adipose tissue and involved in energy homeostasis. Growing evidence suggests that leptin may contribute to the development of cardiac dysfunction. In a large prospective study leptin has been shown to be an independent risk factor for coronary heart disease. An independent positive association has also been found between plasma leptin levels and heart rate in hypertensive patients and heart transplant recipients. In animal studies chronic leptin infusion increased heart rate and blood pressure. It has also been demonstrated that circulating leptin levels are elevated in patients with heart failure. The level of plasma leptin was associated with increased myocardial wall thickness and correlated with left ventricular mass, suggesting a role for this hormone in mediating left ventricular hypertrophy in humans. Moreover, leptin directly induced hypertrophy and hyperplasia in human and rodent cardiomyocytes, accompanied by cardiac extracellular matrix remodelling. Leptin may also influence energy substrate utilisation in cardiac tissue. These findings suggest that leptin acting directly or through the sympathetic nervous system may have adverse effects on cardiac structure and function, and that chronic hyperleptinaemia may greatly increase the risk of cardiac disorders. Additional studies are needed to define the role of leptin in cardiac physiology and pathophysiology, nevertheless the reduction in plasma leptin levels with caloric restriction and weight loss may prevent cardiac dysfunction in obese patients.

High altitude induced anorexia: Effect of changes in leptin and oxidative stress levels

High altitude (HA) exposure usually leads to a significant weight loss in non-acclimatized humans. Anorexia is believed to be the main cause of this body weight loss. Appetite regulatory peptides, i.e. leptin and neuropeptide Y play a key role in food intake and energy homeostasis. Recent studies suggests increased oxidative stress during HA exposure. In present study effect of HA exposure on levels of leptin and NPY was evaluated along with N-acetyl cysteine (NAC) and vitamin E supplementation in relation to food intake and body weight changes. The study was conducted on 30 healthy male volunteers (age 19 – 29 years). Subjects were divided randomly into three groups of 10 each. Group 1 (placebo) supplemented with 400 mg of calcium gluconate, group 2 and 3 were supplemented with 400 mg of NAC and 400 mg vitamin E, respectively per day. The study was conducted at low altitude (320 m, Phase I), at HA 3600 m (Phase II) and at an altitude of 4580 m (Phase III). On HA exposure significant reduction in plasma leptin levels was observed in all the groups on day 2 (Phase II) along with decrease in food intake and reduction in body weight. Statistically significant increase in blood malondialdehyde (MDA) levels was seen in all the groups on HA exposure (Phase II, Day 2), but the maximum increase was in case of placebo group (65.1%) on day 2 (Phase II) in comparison to low altitude values. The decrease in energy intake was almost same in all the groups indicating that antioxidant supplementation did not provide any protection against HA anorexia. From the study, it may be concluded that leptin and oxidative stress possibly are not the key players for HA anorexia.

Behavioral, physiological, and molecular differences in response to dietary restriction in three inbred mouse strains

Food restriction paradigms are widely used in animal studies to investigate systems involved in energy regulation. We have observed behavioral, physiological, and molecular differences in response to food restriction in three inbred mouse strains, C57BL/6J, A/J, and DBA/2J. These are the progenitors of chromosome substitution and recombinant inbred mouse strains used for mapping complex traits. DBA/2J and A/J mice increased their locomotor activity during food restriction, and both displayed a decrease in body temperature, but the decrease was significantly larger in DBA/2J compared with A/J mice. C57BL/6J mice did not increase their locomotor activity and displayed a large decrease in their body temperature. The large decline in body temperature during food restriction in DBA/2J and C57BL/6J strains was associated with a robust reduction in plasma leptin levels. DBA/2J mice showed a marked decrease in white and brown adipose tissue masses and an upregulation of the antithermogenic hypothalamic neuropeptide Y Y(1) receptor. In contrast, A/J mice showed a reduction in body temperature to a lesser extent that may be explained by downregulation of the thermogenic melanocortin 3 receptor and by behavioral thermoregulation as a consequence of their increased locomotor activity. These data indicate that genetic background is an important parameter in controlling an animal's adaptation strategy in response to food restriction. Therefore, mouse genetic mapping populations based on these progenitor lines are highly valuable for investigating mechanisms underlying strain-dependent differences in behavioral physiology that are seen during reduced food availability.

The involvement of IGF-I, leptin and some intracellular signalling mechanisms in nutrition-induced changes in rabbit ovarian cell functions

The aim of our experiments was to examine the role of IGF-I, leptin (the hormone of adipose tissue), in controlling ovarian function in different species, as well as of some protein kinases in mediating IGF-I and leptin effects. In in-vivo experiments, rabbits were subjected to food restriction (50% of normal intake) and IGF-I (2µg/animal) treatments, whilst plasma leptin and IGF-I levels were measured using RIA/EIA. In in-vitro experiments, rabbit ovarian cells were cultured in the presence of leptin, antiserum against IGF-I, inhibitors of MAP kinase and of CDC2 kinase or their combination. Expression of intracellular peptides associated with proliferation (PCNA), apoptosis (bax),CDC2/p34 kinase, cyclin B, protein kinase A, ERK1, 2 MAP kinase, CREB-1 and IGF-I, as well as the secretion of progesterone (P), estradiol (E), IGF-I, and IGFBP-3 were determined using SDS PAGE-Western blotting, immunocytochemistry, RIA and ELISA. Food restriction in rabbits in the periovulatory period results in a significant reduction in plasma leptin levels, which was associated with a significant decrease in IGF-I plasma concentrations. IGF-I addition signicantly increased plasma leptin levels. In in-vitro experiments there was no accumulation of immunoreactive leptin in culture medium conditioned by rabbit granulosa cells. Both leptin and IGF-I additions altered progesterone, estradiol, IGF-I and IGFBP-3 release by cultured granulosa cells, as well as changing the expression of IGF-I, PCNA, bax, protein kinase A, ERK1, 2 MAP kinase, p34 CDC2 kinase, cyclin B and CREB within these cells. Previous food restriction enhanced the response of ovarian cells to leptin and IGF-I treatment. The present observations suggest

Role of ghrelin in streptozotocin-induced diabetic hyperphagia.

Ghrelin, an endogenous ligand for the growth hormone (GH) secretagogue receptor, was originally purified from the rat stomach. We have previously reported that central administration of ghrelin increases food intake and body weight. To investigate the role of ghrelin in the hyperphagic response to uncontrolled diabetes, adult male rats were studied 14 days after administration of streptozotocin (STZ) or vehicle. STZ-treated diabetic rats were markedly hyperphagic. This hyperphagia was accompanied by hyperglycemia, hypoinsulinemia, and reduced plasma GH levels. Treatment of diabetic rats with insulin reversed these changes. Plasma ghrelin concentrations in untreated diabetic rats were significantly higher than in control rats and were normalized by insulin treatment. The ghrelin gene expression in the stomach was also higher in STZ diabetic rats than in control rats, but this difference was not significant. In contrast, plasma leptin was markedly reduced in STZ diabetic rats. This reduction in plasma leptin levels was reversed by insulin treatment. In addition, hypothalamic NPY mRNA levels were increased in STZ-treated diabetic rats and were reversed by insulin treatment. Furthermore, the hyperphagia was partially reversed by the administration of a ghrelin-receptor antagonist. Therefore, we conclude that the elevated plasma ghrelin levels, along with decreased plasma leptin levels, could contribute to the diabetic hyperphagia in part by increasing hypothalamic NPY. This is the first report to show the pathophysiological significance of ghrelin in diabetes.

A role for leptin in the antiaging action of dietary restriction: a hypothesis.

A neuroendocrine signal may play an important role in the antiaging action of dietary restriction (DR). Recent studies have suggested that falling leptin levels by starvation activate the hypothalamic-pituitary-adrenal axis, and suppress gonadal, somatotropic, and thyroid axes as a response for adaptation. Accumulated evidence indicates that similar hormonal changes also occur in DR rodents. In this article, we advance that a reduction in plasma leptin levels in DR rodents might be a critical neuroendocrine modulator in the antiaging action of dietary restriction.