Reduction In Leptin Research Articles

Blocking β-adrenergic signaling attenuates reductions in circulating leptin, cancellous bone mass, and marrow adiposity seen with dietary energy restriction

We tested whether β-adrenergic blockade attenuates bone loss and increased marrow adiposity during energy restriction (ER) and whether such an effect is associated with changes in serum leptin and leptin expression in bone and marrow tissues. Female 4-mo-old Sprague-Dawley rats were assigned into four groups (n = 10 each): two groups of 40% ER treated with vehicle (ERVEH; saline) or β-blocker (ERBB; DL-propranolol; 250 μg · kg(-1) · h(-1)) during 12 wk, and two groups of ad libitum-fed controls treated with the same two agents (CONVEH, CONBB, respectively). Over 84 days, CONVEH and CONBB rats gained but ERVEH and ERBB rats lost body fat mass; lean mass did not change in any group. Reduction in serum leptin in ERVEH rats was mitigated in ERBB rats (-5.32 vs. -1.15 ng/ml, respectively). The decline in proximal tibia cancellous vBMD observed in ERVEH rats was attenuated in ERBB rats (-85.24 vs. -53.94 mg/cm(3), respectively). Adipocyte number in ERVEH rats was dramatically higher vs. CON rats at week 12, but this increment was abolished by β-blockade in ERBB animals. The number of osteoblastic cells and marrow adipocytes staining positively for leptin in ERVEH rats tended to be lower vs. that of both CON groups, but β-blockade appears to reverse this effect in ERBB rats. In summary, β-adrenergic blockade mitigated metaphyseal bone loss and bone marrow adiposity during energy restriction and attenuated reductions in serum leptin. These data suggest an important role for β-adrenoreceptor signaling pathway in the cancellous bone and marrow fat response to energy restriction.

Effect of passive immunization against leptin on ovarian follicular development in prepubertal mice

Leptin has been demonstrated to be essential for reproduction. However, all the relevant studies reported to date have investigated either the effect of a complete absence of leptin both centrally and peripherally, or excess leptin administration. The aim of this present study was to investigate the effect of reducing peripheral leptin concentrations on ovarian follicular development in prepubertal animals via administration of an anti-leptin antibody. Pre-pubertal female mice were administered anti-leptin antibody under the skin behind the head for four days, with or without gonadotropins, and ovaries were weighed and collected for follicle counting. Control animals were treated with non-immune serum. Passive immunization against leptin, with or without gonadotropins, resulted in a significant increase in ovarian weight compared with control ovaries. Furthermore, the ovaries from the anti-leptin group had significantly greater numbers of primary follicles per ovarian section than the control group, thus suggesting an increase in the transition of primordial to primary follicles after treatment. Interestingly, animals treated with anti-leptin plus gonadotropins had a significantly higher number of Graafian follicles in their ovaries compared with the other groups. Collectively, the results of the present study indicate that reduction of leptin in the circulation promotes ovarian follicle development in female mice, suggesting that peripheral leptin acts as an inhibitor of ovarian follicle development.

Effects of Auricular Acupressure Combined with Low-Calorie Diet on the Leptin Hormone in Obese and Overweight Iranian Individuals

Human leptin is a peptide hormone that is released from white adipocytes. The absence of leptin or its receptor leads to uncontrolled food intake, leading to obesity. In the present work, the effects of auricular acupressure combined with low-calorie diet on the leptin hormone level were investigated. Volunteers (n=86) with body mass indices (BMI) between 25 and 45 kg/m² were randomised into a case (n=43) or a control (n=43) group. Participants in each group received a low-calorie diet for 6 weeks. The case group was treated with auricular acupressure and the control group received a sham procedure. Plasma leptin levels, body fat mass, body weight and BMI were measured before and after treatment. Participants who received auricular acupressure showed significant reductions in their plasma leptin levels (18.57%, p<0.01) as well as in their body fat mass (4%, p<0.05). These changes were not observed in the control group. The reduction in leptin was significantly greater in the acupressure group than the controls. Auricular acupressure combined with a low-calorie diet significantly reduced plasma levels of leptin. However, the mechanism of this reduction is not clear.

391 BETA2-ADRENOCEPTOR POLYMORPHISMS (ARG16GLY) IS RELATED TO RESISTANCE TO WEIGHT LOSS INDUCED IMPROVEMENTS OF CARDIAC- AND RENAL COMPLICATIONS

Background: Obesity is an independent risk factor for cardiovascular and renal complications. We previously reported that the Arg16Gly, β2-adrenoceptor (ADRB2) polymorphism, accompanying high plasma norepinephrine (NE) could predict future weight gain, BP elevation and renal injury. The 1st line of treatment for obesity is weight loss (WL). In this study, we evaluated the relationships between ADRB2 polymorphisms (Arg16Gly), prevalence of LVH and renal function (creatinine clearance) over 2 years with WL program. Methods: Obese Japanese men (n = 154) were measured BMI, BP, plasma NE, leptin, creatinine, creatinine clearance (CCr), LVH determined by ECG and ADRB2 polymorphisms (Arg16Gly, Gln27Glu) before and after WL program (low caloric diet + exercise) over 2 years. Significant WL was defined >10% WL of entry BMI. Results: Significant WL was noted in 97 (63%) subjects and the frequencies of Gly16 were 39% for WL group vs. 54% for non-WL group (P < 0.05). At entry, subjects with Gly16 allele had higher levels of plasma NE, leptin, creatinine, higher prevalence of LVH, and lower CCr compared to those without Gly16 allele. WL group had lower fat-mass, NE, leptin and creatinine and LVH prevalence and higher CCr at entry compare dto non-WL group. WL group had greater changes in BMI, fat-mass, creatinine and CCr, and greater % reductions in NE and leptin over a 2-year period. Changes in fat-mass correlated with changes in creatinine, CCr, NE and BP over 2 years. Changes in plasma NE correlated with changes in CCr. In multiple regression analysis, plasma NE, fat-mass and BP levels were determinants for prevalence of LVH at entry and 2-year period. Conclusions: ADRB2 polymorphisms (Arg16Gly) accompanying high plasma NE is related to the prevalence of LVH and improving CCr with WL. Arg16Gly associated with high plasma NE may play an important role in cardio- and renal-complications in obesity.

Effect of a Low-Fat Versus a Low-Gycemic-Load Diet on Inflammatory Biomarker and Adipokine Concentrations

Low-grade inflammation is linked to metabolic syndrome and obesity. We studied the effects of weight loss and dietary composition on serum concentrations of biomarkers of inflammation and adipokines. Men and women (n=181) aged 30-65 years with a body mass index (BMI) of 28-40 kg/m(2) (28-35 kg/m(2) for women) and one or more components of metabolic syndrome were randomized to follow one of two hypocaloric diets, a low-fat or low-glycemic-load diet for 3 months. Blood samples were taken pre- and postintervention. Serum concentrations of interleukin-6 (IL-6), tumor necrosis factorα (TNF-α), plasminogen activator inhibitor-1 (PAI-1), monocyte chemoattractant protein-1 (MCP-1), and adipokines (leptin, resistin, and adiponectin) were analyzed using multiplexed microsphere immunoassays. Weight loss was not different in the low-fat (4.4%±3.8%) and low-glycemic-load (4.9%±3.2%) groups. Concentrations of IL-6, TNF-α, PAI-1, and leptin were significantly reduced in both dietary groups with no between-group differences, whereas MCP-1 and adiponectin concentrations did not change. Subjects with full metabolic syndrome (three or more components; n=109) experienced greater weight loss than subjects (n=72) with one to two components and greater reduction in leptin [7.08 (95% confidence interval 5.19, 8.97) vs. 3.46 (0.91, 6.00) ng/mL; p=0.02] and a tendency to greater reduction in TNF-α (1.00 [0.60, 1.44] vs 0.40 [0.02, 0.78] pg/mL; p=0.05). Hypocaloric diets improved inflammatory biomarkers and adipokines independently of dietary composition. The response tended to be greater in subjects with three or more components of metabolic syndrome than their counterparts with one to two components.

Decreased adrenergic tone in acromegaly: evidence from direct recording of muscle sympathetic nerve activity

Sympathovagal imbalance has been shown in acromegaly by indirect measurements of adrenergic tone. Data regarding direct measurement of sympathetic activity are lacking as yet. Aim of this study was to assess the adrenergic tone through direct recording of muscle sympathetic nerve activity (MSNA) in acromegalic patients. Fifteen patients (age 26-66 years, eight women) with newly diagnosed active acromegaly without hyperprolactinaemia, pituitary hormone deficiencies, obstructive sleep apnoea and cardiac hypertrophy, and 15 healthy subjects matched for age, sex and body mass index were recruited. After evaluating anthropometric and echocardiographic parameters, anterior pituitary function, glucose and lipid metabolism, and measuring plasma leptin, direct recording of sympathetic outflow via the microneurographic technique was performed. For similar anthropometric and metabolic parameters in patients and controls, HOMA index was significantly increased in the former (4·2 ± 2·39 vs 1·6 ± 0·19, P < 0·001). Surprisingly, this finding of insulin resistance was accompanied by a marked sympathetic inhibition (MSNA 18·3 ± 8·10 vs 37·3 ± 6·48 bursts/min, P < 0·0001, respectively in patients and controls). A reduction in plasma leptin (1·6 ± 1·04 vs 6·5 ± 2·01 μg/l, P < 0·0001) was also recorded in the patients. MSNA was positively correlated with leptin (P < 0·0001). Newly diagnosed acromegalic patients without cardiac hypertrophy display a decreased sympathetic outflow in spite of insulin resistance. This finding might be related to hypoleptinaemia.

Short-Term Effects of Sleeve Gastrectomy and Caloric Restriction on Blood Pressure in Diet-Induced Obese Rats

Sleeve gastrectomy constitutes an effective surgical procedure for the treatment of morbid obesity. The aim of the present study was to establish the effects of sleeve gastrectomy and caloric restriction on weight loss and cardiovascular parameters in diet-induced obese (DIO) rats. Male Wistar DIO rats were subjected to surgical interventions (n = 30) (sham operation, sleeve gastrectomy, or pair-fed to the amount of food eaten by sleeve-gastrectomized animals and compared to lean control rats) or dietary interventions (n = 40) (fed ad libitum a normal diet (ND) or a high-fat diet or an ND with a caloric restriction of 25 %). Systolic blood pressure (SBP), diastolic blood pressure, and mean blood pressure values and heart rate (HR) were recorded in conscious, resting animals by noninvasive tail-cuff plethysmography before and 3 weeks after surgical or dietary interventions. Both sleeve gastrectomy and caloric restriction induced a reduction in body weight, whole-body adiposity, and serum leptin together with an increased excess weight loss in DIO rats. Sleeve gastrectomy was further associated with an improvement in insulin resistance and the lipid profile, as well as with a reduction in serum ghrelin levels. A decrease in HR and heart weight was observed in caloric-restricted groups. Sleeve-gastrectomized rats not only exhibited a reduction in HR (∆HR = -45 ± 19 bpm) but also in SBP values (∆SBP = -22 ± 10 mmHg) compared to the DIO rats (∆SBP = 14 ± 8 mmHg). Our findings provide evidence that the beneficial effects of sleeve gastrectomy on blood pressure values are beyond weight loss in rats with diet-induced obesity.

Physical activity and breast cancer

Knowledge of the relationships between risks and benefits of a given lifestyle is fundamental to being able to change life-long habits responsible for the development of pathological processes. Breast cancer is a widely studied pathology of vast social importance. It is important to identify the most appropriate lifestyle to give the organism the necessary tools to prevent tumour development. Physical exercise can act on and modify the different risk factors responsible for the development of both the primary pathology of breast cancer and relapses, thus reducing mortality. The various hypotheses of the biological routes through which physical activity can reduce risk indicate involvement of the following mechanisms: reduction in body weight, reduction in circulating levels of sex hormones, reduction in insulin resistance, reduction in leptin and adiponectin and modulation of the immune system. Recent discoveries on the mechanisms of cancer development indicate that cancer is the chronic pathology par excellence, and it is highly unlikely that it will be possible to eliminate it by concentrating all our efforts on tumour treatment techniques alone; it will be necessary to cure the whole organism in depth. Physical activity can be considered an “anticancer biology” that succeeds in exploiting the breakthroughs of medicine and our natural defences.

Inflammatory and metabolic changes of severe obese women after 6 months of a Roux‐en‐Y gastric bypass

Obesity is a chronic disease related to adipokines production, which contribute to inflammation and metabolic abnormalities. The Roux‐en‐Y gastric bypass is an alternative therapy for the treatment of severe obesity, reaching weight loss superior to conventional therapies. The aim was observed the inflammatory and metabolic changes after 6 months of Roux‐en‐Y gastric bypass. Nine women aged 24 – 48 years old, BMI &gt; 35 kg/m2 (50.9±9.6), submitted to Roux‐en‐Y gastric bypass. Plasma concentrations evaluated: glucose (mg/dL), leptin (pg/mL), adiponectin (ng/mL), TNF‐α (pg/mL) and IL‐6 (pg/mL). Anthropometric assessment: weight (kg), BMI (kg/m2) and fat mass (FM: kg). We observed reduction in body weight (130.1±23.8 × 98.5±25.2, p&lt;0.01) and FM (72.1±17.4 × 40.8±8.3, p&lt;0.01). Significant metabolic changes were found, such as reduction in leptin [431.3 (303.8 – 532.2) × 96.7 (62.0 – 176.8), p&lt;0.01] and glucose [97.0 (84.5 – 107.5) × 82.0 (74.7 – 85.0), p=0.04] and increased adiponectin (62.7±21. 2 × 206.0±120.8, p&lt;0.01). With respect to pro‐inflammatory parameters, no significant changes were observed in TNF‐α (0.44±0.69 × 0.3±0.5, p=0.20) and IL‐6 [4.7 (3.2 – 7.6) × 1.8 (0.9 – 3.8), p=0.12]. Six months after surgery decreased fat mass and resulting in changes as decreased leptin and glucose and increased adiponectin. In other hand in this period there was no change in inflammatory parameters.

Role of General Control Nonderepressible 2 (GCN2) kinase in mediating responses to dietary methionine restriction

Restriction of dietary methionine from normal levels (0.86%) to 0.17% produces a coordinated series of biochemical and physiological responses that improve biomarkers of metabolic health, limit fat accretion, and enhance insulin sensitivity. GCN2 kinase serves as a sensor to detect reductions in essential amino acids and initiates integrated behavioral and transcriptional responses that mediate metabolic adaptation. The role of GCN2 in mediating the responses to dietary methionine restriction (MR) was assessed using GCN2−/− mice. Dietary MR for 8 wks produced a comparable reduction in hepatic triglyceride and increase in food consumption in wild type (WT) and GCN2−/− mice, while the normal diet‐induced increase in plasma adiponectin was actually enhanced in GCN2 nulls. The transcriptional responses produced by dietary MR in brown adipose tissue did not differ between WT and GCN2 null mice. In contrast, the diet‐induced increase in energy expenditure and reductions in fasting insulin and hepatic SCD‐1 expression observed in WT mice were partially compromised in GCN2 nulls, and the normal reductions in adiposity, plasma leptin and glucose were absent in GCN2−/− mice. The present findings suggest that GCN2 is an important component of the nutrient sensing mechanism(s) linking restriction of dietary methionine to the metabolic adaptations produced by the diet. Work supported by NIH: 2 P20 RR021945 (TWG), 2 U24 DK076169 (TWG), 1 F32 DK088513 (EPP), 1 RO1 HD070487 (TGA).Grant Funding Source: NIH

New Mutations at the Imprinted Gnas Cluster Show Gene Dosage Effects of Gsα in Postnatal Growth and Implicate XLαs in Bone and Fat Metabolism but Not in Suckling

The imprinted Gnas cluster is involved in obesity, energy metabolism, feeding behavior, and viability. Relative contribution of paternally expressed proteins XLαs, XLN1, and ALEX or a double dose of maternally expressed Gsα to phenotype has not been established. In this study, we have generated two new mutants (Ex1A-T-CON and Ex1A-T) at the Gnas cluster. Paternal inheritance of Ex1A-T-CON leads to loss of imprinting of Gsα, resulting in preweaning growth retardation followed by catch-up growth. Paternal inheritance of Ex1A-T leads to loss of imprinting of Gsα and loss of expression of XLαs and XLN1. These mice have severe preweaning growth retardation and incomplete catch-up growth. They are fully viable probably because suckling is unimpaired, unlike mutants in which the expression of all the known paternally expressed Gnasxl proteins (XLαs, XLN1 and ALEX) is compromised. We suggest that loss of ALEX is most likely responsible for the suckling defects previously observed. In adults, paternal inheritance of Ex1A-T results in an increased metabolic rate and reductions in fat mass, leptin, and bone mineral density attributable to loss of XLαs. This is, to our knowledge, the first report describing a role for XLαs in bone metabolism. We propose that XLαs is involved in the regulation of bone and adipocyte metabolism.

Leptin, Cortisol and Distinct Concurrent Training Sequences

In order to investigate the effects of distinct concurrent training sequences on serum leptin and cortisol levels, 10 subjects (27.1±4.8 years, body mass index 25.38±0.09) were submitted to a control session, concurrent training 1 and concurrent training 2. Samples of leptin and cortisol were collected. Concurrent training 1 consisted of indoor cycling followed by strength training and concurrent training 2 of strength training followed by indoor cycling. No exercises were performed at the control session. Blood was collected once again to verify the same variables. Shapiro-Wilk, 2-way ANOVA and Tukey post-hoc tests were used. There was a reduction in leptin levels after concurrent training 1 (Δ%= - 16.04; p=0.05) and concurrent training 2 (Δ%= - 8.54; p=0.02). Cortisol decreased after concurrent training 1 (Δ%= - 26.32; p=0.02) and concurrent training 2 (Δ%= - 33.57; p=0.05). There was a high and significant correlation between blood variables only in CS (lep PRE X cort PRE and cort POST: r= - 0.80 and r= - 0.81; lep POST X cort PRE and cort POST: r= - 0.62 and r= - 0.62). Concurrent training promoted a reduction in leptin and cortisol levels irrespective of sequence.

Metformin; A character actor in the leptin story!

Our current understanding of metabolic processes tells us that there is more to the control of eating behavior then mere stimulation by hunger and hedonic sensation. How brain in general and hypothalamus in particular interacts with peripheral tissue to control feeding has remained a subject of intensive scientific discussions. Lessons learnt from rare but distinctive mongentic disorders causing extreme obesity have turned the spotlight on hypothalamo-leptin-melanocortin system. And that is how the leptin story began, taking other factors along in its course.[1] Metformin, a biguanide, has been as a first line drug of choice along with lifestyle intervention in the management of type 2 diabetic patients. It seems this molecule has been assigned to play the role of a protagonist in the story of management of T2DM. This superstar status won by a drug discovered half a century ago by Professor Jeanne Sterne is though extraordinary, did not come without struggle. To quote Professor Gerald Slama and Professor Ian Campbell, two pioneers who worked on this molecule extensively through the recent decades, “The metformin journey is one of the discovery, dismissal and re-discovery and its very survival is due to some defining moments over the past 50 years.”[2] How do we combine these two interesting stories. Do we have a substantial plot to find this wonderful molecule playing an important character role in modifying defect(s) in the leptin actions. Metformin induced reduction in leptin level in morbidly obese individuals has been proven in several studies, but some others have shown evidence to the contrary.[3–6] Possible explanations for these discrepancies may be the length of treatment and the study population, with obese people showing a decrease in leptin levels after long-term treatment. On metformin, there were linear trends in decrements in weight, girth, waist circumference, waist/hip ratio, insulin, and leptin. Reduction in leptin paralleled the reduction in insulin levels and somewhat greater in those with higher baseline serum leptin.[3] Interestingly, distinct reduction in serum leptin level was observed in non obese healthy individual on metformin, without any reduction in body weight.[4] Hence, the scientific community is trying to look beyond changes in adipocyte morphology in trying to define the role of metformin in leptin biology.[7] More recently, it has been demonstrated that weight loss achieved by metformin was correlated with pretreatment plasma leptin levels. This effect of metformin was paralleled by a stimulation of the expression of the leptin receptor gene (ObRb) in the arcuate nucleus, thus identifying the hypothalamic ObRb as a gene modulated after metformin treatment.[8] It has suggested that the anorectic effects of metformin are potentially mediated via an increase in the central sensitivity to leptin. Thus, the time is just right and ripe to assign another pioneering role, at least of a character actor, if not the protagonist, for metformin in the story of leptin biology. As scientists travel to the deeper realms of the subject and write and rewrite the story for the medical community at large, the people involved in the editorial task of this issue will continue to derive satisfaction of not missing it out, and of course doing a job on-time.

Influence of Weight Loss, Body Composition, and Lifestyle Behaviors on Plasma Adipokines: A Randomized Weight Loss Trial in Older Men and Women with Symptomatic Knee Osteoarthritis

Objective. To investigate effects of weight loss on adipokines and health measures in obese older adults with symptomatic knee osteoarthritis. Methods. Participants were randomly assigned to either weight loss (WL) (men: 12, women: 14) or weight stable (WS) group (men: 12, women: 13). WL intervention included meal replacements and structured exercise training. Measurements of leptin, adiponectin, soluble leptin receptor, lifestyle behaviors, and body composition were collected at baseline and 6 months. Univariate analysis of covariance was performed on 6 month variables, and Spearman and partial correlations were made between variables. Results. Weight loss was 13.0% and 6.7% in WL for men and women, respectively. Women in WL had lower whole body and trunk fat than WS. The leptin : adiponectin ratio was lower for women in WL than WS at 6 months, with no group differences in adipokines for men. Leptin and free leptin index correlated with body fat in both genders at baseline. Interestingly, only women showed reductions in leptin (P < 0.100) and correlations between the percentage change leptin and trunk fat and the percentage changes in free leptin index with total fat and trunk fat. Partial correlations between 6 month adipokines after adjustments for covariates and group/time period show potential multivariate influences. Conclusions. In the presence of an effective weight loss intervention in older obese adults, there are significant relationships between weight and fat loss and leptin in women, but not men, suggesting gender-specific features of adipokine metabolism in this age group.

Light Modulates Leptin and Ghrelin in Sleep-Restricted Adults

Acute and chronic sleep restrictions cause a reduction in leptin and an increase in ghrelin, both of which are associated with hunger. Given that light/dark patterns are closely tied to sleep/wake patterns, we compared, in a within-subjects study, the impact of morning light exposures (60 lux of 633-nm [red], 532-nm [green], or 475-nm [blue] lights) to dim light exposures on leptin and ghrelin concentrations after subjects experienced 5 consecutive days of both an 8-hour (baseline) and a 5-hour sleep-restricted schedule. In morning dim light, 5-hour sleep restriction significantly reduced leptin concentrations compared to the baseline, 8-hour sleep/dim-light condition (t 1,32 = 2.9; P = 0.007). Compared to the 5-hour sleep/dim-light condition, the red, green, and blue morning light exposures significantly increased leptin concentrations (t 1,32 = 5.7; P < 0.0001, t 1,32 = 3.6; P = 0.001, and t 1,32 = 3.0; P = 0.005, resp.). Morning red light and green light exposures significantly decreased ghrelin concentrations (t 1,32 = 3.3; P < 0.003 and t 1,32 = 2.2; P = 0.04, resp.), but morning blue light exposures did not. This study is the first to demonstrate that morning light can modulate leptin and ghrelin concentrations, which could have an impact on reducing hunger that accompanies sleep deprivation.

Dietary glycemic index/load and peripheral adipokines and inflammatory markers in elderly subjects at high cardiovascular risk

Background and AimsEpidemiological and clinical studies suggest that low-glycemic index diets could protect against weight gain. However, the relationship between these diets and adipokines or inflammatory markers is unclear. In the present study we examine how the dietary glycemic index (GI) and dietary glycemic load (GL) are associated with several adipokines and related metabolic risk markers of obesity and diabetes in a cross-sectional and longitudinal manner. Methods and Results511 elderly community-dwelling men and women at high cardiovascular risk were recruited for the PREDIMED trial. Dietary data were collected at baseline and after 1 year of follow-up. The GI and GL were calculated. Plasma leptin, adiponectin and other metabolic risk markers were measured at baseline and after 1 year. At baseline, subjects in the highest quartiles of GI showed significantly higher levels of TNF and IL-6 than those in the lowest quartiles. Dietary GI index was negatively related to plasma leptin and adiponectin levels. After 1 year of follow-up, subjects with a higher increase in dietary GI or GL showed a greater reduction in leptin and adiponectin plasma levels. There was no association between GI or GL and the other metabolic markers measured. ConclusionOur results suggest that the consumption of high-GI or high-GL diets may modulate plasma concentrations of leptin and adiponectin, both adipostatic molecules implicated in energy balance and cardiometabolic risk.

Abstract 9849: Aerobic Exercise Improves Endothelial Dysfunction in Pre-Diabetes Patients

Current literature confirms presence of endothelial cell dysfunction in diabetes compared to non-diabetes state. However there is lack of data on endothelial function in Pre-diabetes (defined as per Diabetes Care, Clinical Guideline, Jan'11 ). Methods: We selected exercise-naive patients, 20-70 yrs, BMI 25-34.9, n=20 in each group and studied their endothelial function after 150min/week of aerobic exercise (similar to Diabetes Prevention Program) and after non exercise phase (6wks phase each), in a cross over design with a 4 wk wash-out period between the 2 groups. For endothelial function assessment we looked at, 1. flow mediated dilatation (FMD of brachial artery), 2. CD34/KDR +ve cell count from peripheral blood derived mononuclear cell fraction at day0 by Flow cytometry (FACS) 3. endothelial progenitor cell (EPC) associated colony-forming units (Hill-CFU) at day5 of culture, 4.endothelial bio-inflammatory markers and BP, fasting lipids, insulin, glucose. We also looked at gene expression profile of critical endothelial function genes in CD34/KDR+ve cells. Results: FMD studies (undertaken by 3 observers, blinded to glycemic status) showed, mean FMD in non-exercise group of 5.7+0.6% and post exercise it improved to 11.2±0.9%. Both CFU estimation, at day5 and CD34/KDR +ve cells estimation at day0 showed significant increase in numbers following exercise. There was no weight loss noted between 2 groups, however, there was statistically significant reduction in leptin, IL-6, TNFα, fasting Triglyceride, LDL and ApoB levels. Insulin sensitivity (HOMA) improved in the exercise group. Gene expression analysis of CD34+ve cells showed decrease of eNOS and increase of PECAM-1 in non-exercise which improved significantly following exercise, with no change in von-Willebrand's factor. Summary: Prediabetic patients have significant endothelial dysfunction, similar to patients with diabetes. In this population, FMD measurements and CD34/KDR+ve cell number and gene profile assays along with usual biochemical markers can serve as robust bio-markers for monitoring endothelial cell dysfunction. Conclusion: Pre-diabetic state is associated with significant endothelial dysfunction which can be improved, by undertaking regular aerobic exercise.

Prolactin Activation of the Long Form of its Cognate Receptor Causes Increased Visceral Fat and Obesity in Males as Shown in Transgenic Mice Expressing only this Receptor Subtype

To date the best defined function of prolactin (PRL) is its action on the ovary and mammary gland, although it has also been shown to have an effect on lipid metabolism. Using mice engineered to express only the long form of the prolactin receptor (PRL-RL), we demonstrate that PRL acting through PRL-RL alone causes severe adipose accumulation in visceral fat of males at 6 months of age. The increase in visceral fat accumulation is attributed to loss of adipose-derived leptin, which results in diminished lipolysis. The reduction in leptin also corresponds to decreased activation of AMP-activated protein kinase (AMPK), which further results in diminished fatty acid oxidation and increased fatty acid synthesis. Interestingly, the blunted AMPK response was only observed in adipose tissue and not in liver suggesting that this PRL mediated effect is tissue specific. A glucose tolerance study inferred that PRL-RL mice may suffer from insulin resistance or a reduction in insulin production that is not due to aberrant expression of glucose transporter 4 (Glut4). Collectively, our findings demonstrate that PRL signaling through the long form receptor causes reduced fatty acid oxidation, increased lipid storage, glucose intolerance, and obesity. These findings are of great importance towards understanding the etiology of obesity associated with hyperprolactinemia in humans as well as the role of PRL as a metabolic regulator in adipose tissue.

Effects of Acute Changes in Neonatal Leptin Levels on Food Intake and Long-Term Metabolic Profiles in Rats

In rodents there is a rise in serum leptin levels between postnatal days (PND) 5 and 14, with this neonatal leptin surge reported to modulate the maturation of hypothalamic circuits involved in appetite regulation. We hypothesized that acute changes in neonatal leptin levels have different long-term metabolic effects depending on how and when this surge is modified. To advance the timing of the normal leptin peak, male Wistar rats were injected with leptin (sc, 3 μg/g) on PND 2. To ablate the leptin peak on PND 10, a pegylated leptin antagonist (sc, 9 μg/g) was injected. Controls received vehicle. All rats were allowed to eat ad libitum until PND 150. Increased leptin on PND 2 reduced food intake (P<0.01) after 3 months of age with no effect on body weight. Levels of total ghrelin were reduced (P<0.001) and acylated ghrelin increased (P<0.05), with no other modifications in metabolic hormones. In contrast, treatment with the leptin antagonist on PND 9 did not affect food intake but reduced body weight beginning around PND 60 (P<0.02). This was associated with a reduction in fat mass, insulin (P<0.01), and leptin (P<0.007) levels and an increase in testosterone levels (P<0.01). Hypothalamic neuropeptide Y (P<0.05) and leptin receptor (P<0.005) mRNA levels were reduced, whereas mRNA levels for uncoupling protein 2 (P<0.005) were increased in visceral fat, which may indicate an increase in energy expenditure. In conclusion, acute changes in neonatal leptin levels induce different metabolic profiles depending on how and when leptin levels are modified.

Metabolic Impact of Growth Hormone Treatment in Short Children Born Small for Gestational Age

Background: Growth hormone (GH) treatment in short children born small for gestational age (SGA) may result in metabolic changes with potential long-term effects. Methods: 149 short SGA children (mean birth weight 2.0 ± 0.6 kg, age 5.5 ± 1.5 years, height standard deviation score (SDS) –3.1 ± 0.6) were randomised to: low-dose GH therapy (0.033 mg/kg/day) for 2 years; high-dose GH therapy (0.100 mg/kg/day) for 1 year, or mid-dose GH therapy (0.067 mg/kg/day) for 1 year. Leptin, ghrelin, insulin-like growth factor-I (IGF-I), IGF binding protein-1 (IGFBP-1), lipids, fasting blood glucose and fasting insulin were assessed at baseline, 12 and 24 months. Results: After 1 year of active treatment, GH significantly reduced serum ghrelin and increased IGF-I SDS and insulin levels. Regression analysis showed an inverse correlation between ghrelin and IGF-I SDS (p < 0.001). Leptin and IGFBP-1 also declined (both p < 0.05). Changes in insulin levels reversed upon discontinuation. Improvements in lipid profile were nonsignificant and fasting blood glucose levels remained within the normal range. Conclusion: In short SGA children, ghrelin and leptin reductions associated with GH treatment may occur through a negative feedback loop of the GH–IGF-I axis. Consequently, via ghrelin and leptin suppression, GH treatment may modify food intake and body composition and potentially improve long-term metabolic outcomes.