In vivo and ex vivo regulation of visfatin production by leptin in human and murine adipose tissue : role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways

Visfatin is an adipogenic adipokine with increased levels in obesity, properties common to leptin. Thus, leptin may modulate visfatin production in adipose tissue (AT). Therefore, we investigated the effects of leptin on visfatin levels in 3T3-L1 adipocytes and human/murine AT, with or without a leptin antagonist. The potential signaling pathways and mechanisms regulating visfatin production in AT was also studied. Real-time RT-PCR and Western blotting were used to assess the relative mRNA and protein expression of visfatin. ELISA was performed to measure visfatin levels in conditioned media of AT explants, and small interfering RNA technology was used to reduce leptin receptor expression. Leptin significantly (P < 0.01) increased visfatin levels in human and murine AT with a maximal response at leptin 10–9 M, returning to baseline at leptin 10–7 M. Importantly, ip leptin administration to C57BL/6 ob/ob mice further supported leptin-induced visfatin protein production in omental AT (P < 0.05). Additionally, soluble leptin receptor levels rose with concentration dependency to a maximal response at leptin 10–7 M (P < 0.01). The use of a leptin antagonist negated the induction of visfatin and soluble leptin receptor by leptin. Furthermore, leptin-induced visfatin production was significantly decreased in the presence of MAPK and phosphatidylinositol 3-kinase inhibitors. Also, when the leptin receptor gene was knocked down using small interfering RNA, leptin-induced visfatin expression was significantly decreased. Thus, leptin increases visfatin production in AT in vivo and ex vivo via pathways involving MAPK and phosphatidylinositol 3-kinase signaling. The pleiotropic effects of leptin may be partially mediated by visfatin

Plasma Leptin Levels and Incidence of Heart Failure, Cardiovascular Disease, and Total Mortality in Elderly Individuals

OBJECTIVE: Obesity predisposes individuals to congestive heart failure (CHF) and cardiovascular disease (CVD). Leptin regulates energy homeostasis, is elevated in obesity, and influences ventricular and vascular remodeling. We tested the hypothesis that leptin levels are associated with greater risk of CHF, CVD, and mortality in elderly individuals. RESEARCH DESIGN AND METHODS: We evaluated 818 elderly (mean age 79 years, 62% women) Framingham Study participants attending a routine examination at which plasma leptin was assayed. RESULTS: Leptin levels were higher in women and strongly correlated with BMI (P < 0.0001). On follow-up (mean 8.0 years), 129 (of 775 free of CHF) participants developed CHF, 187 (of 532 free of CVD) experienced a first CVD event, and 391 individuals died. In multivariable Cox regression models adjusting for established risk factors, log-leptin was positively associated with incidence of CHF and CVD (hazard ratio [HR] per SD increment 1.26 [95% CI 1.03–1.55] and 1.28 [1.09–1.50], respectively). Additional adjustment for BMI nullified the association with CHF (0.97 [0.75–1.24]) but only modestly attenuated the relation to CVD incidence (1.23 [1.00–1.51], P = 0.052). We observed a nonlinear, U-shaped relation between log-leptin and mortality (P = 0.005 for quadratic term) with greater risk of death evident at both low and high leptin levels. CONCLUSIONS: In our moderate-sized community-based elderly sample, higher circulating leptin levels were associated with a greater risk of CHF and CVD, but leptin did not provide incremental prognostic information beyond BMI. Additional investigations are warranted to elucidate the U-shaped relation of leptin to mortality.National Institutes of Health's National Heart, Lung, and Blood Institute (N01-HC25195, N01-HV28178, K24-HL04334, R01-DK080739

Adiponectin, in contrast to leptin, is not associated with body mass index, waist circumference and HOMA-IR in subjects of a west-African population

Factors associated with plasma levels of adiponectin and leptin were studied in adult subjects without diabetes from Cotonou in Benin (West‐Africa). Seventy (70) men and 45 women were included in the study. Anthropometric variables were measured and a venous blood sample was drawn from each subject, after an overnight fasting period, for measurement of plasma glucose, insulin, leptin, and adiponectin levels. HOMA‐IR was determined to assess insulin resistance. Adiponectin and leptin levels were higher in women than in men (with adiponectin 18.48 ± 12.77 vs.7.8 ± 10.39 μg/mL, P &lt; 0.0001, and leptin 30.77 ± 19.16 vs. 8.66 ± 8.24 ng/mL, P &lt; 0.0001). Fasting insulin level and HOMA‐IR were also higher in the females. Hyperleptinemia was observed in 66,96% of subjects and hypoadiponectinemia was present in 44.35% of subjects. In both men and women, leptin correlated with age (r = 0.2; P = 0.02), BMI (r = 0.572; P &lt; 0.0001), waist circumference (r = 0.534; P &lt; 0.0001), fasting insulin (r = 0.461; P &lt; 0.001), and HOMA‐IR (r = 0.430; P &lt; 0.0001). No significant correlation was observed for adiponectin levels with these variables. Only in women, adiponectin was inversely correlated with fasting glucose (r = −0.423; P &lt; 0.004). These data confirm previous descriptions of leptin but suggest that variations in factors determining serum adiponectin levels observed between ethnicities could also been seen between populations from the same ethnicity

High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids.

BackgroundPatients with systemic lupus erythematosus (SLE) are at increased risk of atherosclerosis, even after accounting for traditional risk factors. High levels of leptin and low levels of adiponectin are associated with both atherosclerosis and immunomodulatory functions in the general population.ObjectiveTo examine the association between these adipokines and subclinical atherosclerosis in SLE, and also with other known inflammatory biomarkers of atherosclerosis.MethodsCarotid ultrasonography was performed in 250 women with SLE and 122 controls. Plasma leptin and adiponectin levels were measured. Lipoprotein a (Lp(a)), oxidised phospholipids on apoB100 (OxPL/apoB100), paraoxonase, apoA-1 and inflammatory high-density lipoprotein (HDL) function were also assessed.ResultsLeptin levels were significantly higher in patients with SLE than in controls (23.7±28.0 vs 13.3±12.9 ng/ml, p&lt;0.001). Leptin was also higher in the 43 patients with SLE with plaque than without plaque (36.4±32.3 vs 20.9±26.4 ng/ml, p=0.002). After multivariate analysis, the only significant factors associated with plaque in SLE were leptin levels in the highest quartile (≥29.5 ng/ml) (OR=2.8, p=0.03), proinflammatory HDL (piHDL) (OR=12.8, p&lt;0.001), age (OR=1.1, p&lt;0.001), tobacco use (OR=7.7, p=0.03) and hypertension (OR=3.0, p=0.01). Adiponectin levels were not significantly associated with plaque in our cohort. A significant correlation between leptin and piHDL function (p&lt;0.001), Lp(a) (p=0.01) and OxPL/apoB100 (p=0.02) was also present.ConclusionsHigh leptin levels greatly increase the risk of subclinical atherosclerosis in SLE, and are also associated with an increase in inflammatory biomarkers of atherosclerosis such as piHDL, Lp(a) and OxPL/apoB100. High leptin levels may help to identify patients with SLE at risk of atherosclerosis

Leptin fails to blunt the lipopolysaccharide-induced activation of the hypothalamic-pituitary-adrenal axis in rats

Copyright @ 2013 The authors. This work is licensed under a Creative Commons Attribution 3.0 Unported License.Obesity is a risk factor for sepsis morbidity and mortality, whereas the hypothalamic-pituitary-adrenal (HPA) axis plays a protective role in the body's defence against sepsis. Sepsis induces a profound systemic immune response and cytokines serve as excellent markers for sepsis as they act as mediators of the immune response. Evidence suggests that the adipokine leptin may play a pathogenic role in sepsis. Mouse endotoxaemic models present with elevated leptin levels and exogenously added leptin increased mortality whereas human septic patients have elevated circulating levels of the soluble leptin receptor (Ob-Re). Evidence suggests that leptin can inhibit the regulation of the HPA axis. Thus, leptin may suppress the HPA axis, impairing its protective role in sepsis.We hypothesised that leptin would attenuate the HPA axis response to sepsis.We investigated the direct effects of an i.p. injection of 2 mg/kg leptin on the HPA axis response to intraperitoneally injected 25 μg/kg lipopolysaccharide (LPS) in the male Wistar rat. We found that LPS potently activated the HPA axis, as shown by significantly increased plasma stress hormones, ACTH and corticosterone, and increased plasma interleukin 1β (IL1β) levels, 2 h after administration. Pre-treatment with leptin, 2 h before LPS administration, did not influence the HPA axis response to LPS. In turn, LPS did not affect plasma leptin levels. Our findings suggest that leptin does not influence HPA function or IL1b secretion in a rat model of LPS-induced sepsis, and thus that leptin is unlikely to be involved in the acute-phase endocrine response to bacterial infection in rats.The section is funded by grants from the MRC, BBSRC, NIHR and an Integrative Mammalian Biology (IMB) Capacity Building Award, and by a FP7-HEALTH-2009-241592 EuroCHIP grant and is supported by the NIHR Imperial Biomedical Research Centre Funding Scheme. This work is supported by a BBSRC Doctoral Training-Strategic Skills Award grant (BB/F017340/1)

Study of Serum Leptin in Well-differentiated Thyroid Carcinoma: Correlation with Patient and Tumor Characteristics

Background There is a proven relationship between obesity and several cancers including breast, endometrium, colorectal, and esophagus. With the increasing incidence of both obesity and thyroid cancer, we designed the present study to investigate a causal relationship between leptin, which is one of the well known adipokines, and well-differentiated thyroid cancer (WDTC). Methods Serum leptin levels were measured in 30 patients with WDTC and compared to 30 healthy control subjects before and 1 month after surgery. Other parameters studied included age, sex, body mass index, menopausal status in women, lymph node status, tumor size, and disease multifocality. Results There were no differences between the two groups regarding age and sex. Preoperative leptin levels were higher in the WDTC patients when compared to the control patients [19.25 (1.50–109.60) vs 0.90 (0.50–11.80) ng/ml, p < 0.001, group 1 vs group 2, respectively]. A significant drop in leptin levels 1 month after surgery occurred in the WDTC group, falling from 19.25 (1.50–109.60) to 0.90 (0.60–8.90) ng/ml (p < 0.001). This did not occur in the control group (p = 0.274). Lymph node involvement, tumor size, and multifocality had no effect on leptin levels, although trends were observed (p = 0.48, 0.079, and 0.064), respectively. Conclusions Serum leptin levels were significantly higher in WDTC patients when compared to control group patients, with a significant drop after surgery. Leptin may play a role in diagnosis of WDTC; however, its prognostic value is still undetermined

Leptin receptor in the chicken ovary: potential involvement in ovarian dysfunction of ad libitum-fed broiler breeder hens

In hens, the ovarian follicles committed to ovulation are arranged in an ordered follicular hierarchy. In standard broiler breeders hens genetically selected for high growth rate the reproductive function is clearly dysfunctional. Feed restriction is needed during reproductive development to limit the formation of excessive numbers of ovarian yellow follicles arranged in multiple hierarchies. To determine whether leptin is involved in the nutritional and reproductive interactions controlling follicular hierarchy in hens, blood leptin levels and ovarian expression of the leptin receptor mRNA were determined during follicle maturation in three chicken lines; a slow growing broiler "Label" genotype without reproductive dysfunction, a fast growing "Standard" genotype fed ad libitum or restricted and a fast growing "Experimental" line with intermediate reproductive performance levels. Whereas expression of the leptin receptor mRNA did not change in the theca, it clearly decreased with follicular differentiation in the granulosa of slow growing hens. In fast growing standard hens fed ad libitum and presenting significant reproductive dysfunction, the decrease was disrupted and dramatic up-regulation of granulosa cell expression of the leptin receptor was observed. On the other hand, feed restriction decreased the overall level of expression of the leptin receptor mRNA and restored the decrease with follicular growth. The level of expression of the leptin receptor probably modulates the action of leptin on follicular differentiation. Since blood leptin and other metabolic factors were not affected by the genotype or by nutritional state, the factors involved in the regulation of leptin receptor gene expression remain to be determined. This study demonstrates the involvement of leptin in the nutritional control of reproduction in birds. Leptin action on the ovary probably controls follicular hierarchy through the regulation of steroidogenesis

Mouse circadian plasma leptin and active ghrelin rhythms under ad libitum and scheduled feeding

Thesis (M.S.) University of Alaska Fairbanks, 2007Light is the strongest timing cue for the circadian system, but non-photic cues can also entrain the master circadian clock, i.e., suprachiasmatic nuclei (SCN). In one of our mouse line (ENTR), all mice entrain to scheduled feeding, while in another (NON-ENTR) only 4 % entrain. In order to explore key physiological pathways involved in that process, I quantified the circadian rhythms of plasma leptin and active ghrelin of these two lines of mice under a 12:12 hour light-dark cycle with ad libitum feeding and six hours of food availability during the light period. Plasma active ghrelin induced opposite circadian rhythms compared to leptin, which were most pronounced under scheduled feeding when leptin was highest during and right after the food availability period; active ghrelin was highest at night when food was not available. Compared to ad libitum feeding, the overall concentration of leptin decreased and active ghrelin concentration increased significantly under scheduled feeding. The plasma active ghrelin circadian rhythms of ENTR mice were more robust with higher amplitude rhythms than the NON-ENTR mice under ad libitum feeding and scheduled feeding. I hypothesize that the high amplitude plasma active ghrelin circadian rhythm provides a signal for the ENTR mice to entrain to scheduled feedingIntroduction -- Materials and methods -- Animals under ad libitium feeding -- Animals under scheduled-feeding -- Procedure for obtaining blood samples -- Biochemical analysis -- Statistics -- Results -- Body weight -- Plasma leptin concentrations -- Plasma active ghrelin concentrations -- Behavioral entrainment to scheduled feeding -- Discussion --Circadian plasma leptin levels under different feeding conditions -- Circadian plasma ghrelin levels under different feeding conditions -- Relationship between circadian plasma leptin and active ghrelin levels after scheduled feeding -- Conclusions -- Literature cited