Adipose Tissue-derived Factor Research Articles

Serum leptin level and incidence of CKD: a longitudinal study of adult enrolled in the Korean genome and epidemiology study(KoGES)

BackgroundChronic kidney disease(CKD) is a major public health issue and is highly prevalent in the general population. Leptin is an adipose tissue-derived endocrine factor that has been associated with several metabolic factors involved in cardiovascular diseases. Several studies have investigated the association between leptin and renal diseases so far. But the results are conflicting between the studies. The objective of our study was to verify the direct association of serum leptin level with CKD development.MethodsThis prospective cohort study included 2646 adult aged 40–70 without CKD in the Korean Genome and Epidemiology Study(KoGES) across South Korea from November 2005 to February 2012. The primary outcome was the development of CKD as defined by National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI). Multivariate stepwise logistic regression analysis was done to assess the independent associations, for with the incident of CKD as the dependent variable, in tertiles of leptin values.ResultsAmong 1100 men and 1546 women with 2.8 mean years of follow-up, incidence of CKD was 18(1.63%) for men and 50(3.23%) for women. In the multivariate logistic regression models, individuals in the highest serum leptin tertile showed significant associations with risk of CKD after adjustment compared to the lowest tertiles in the population. The crude odds ratio for trend was 2.95(p = 0.004) for men. After adjusting for age, baseline eGFR variables showed correlation with statistical significance (OR for trend = 2.25, p = 0.037) for men. The same trends were also seen observed in all population and women also, but no statistical significance was found.ConclusionsHigher plasma leptin levels are associated with the incidence of CKD, independent of traditional factors such as age, baseline eGFR. Our results suggest that leptin may partly explain part of the reported association between obesity and kidney disease.

Adipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue

Activation of brown fat thermogenesis increases energy expenditure and alleviates obesity. Sympathetic nervous system (SNS) is important in brown/beige adipocyte thermogenesis. Here we discover a fat-derived “adipokine” neurotrophic factor neurotrophin 3 (NT-3) and its receptor Tropomyosin receptor kinase C (TRKC) as key regulators of SNS growth and innervation in adipose tissue. NT-3 is highly expressed in brown/beige adipocytes, and potently stimulates sympathetic neuron neurite growth. NT-3/TRKC regulates a plethora of pathways in neuronal axonal growth and elongation. Adipose tissue sympathetic innervation is significantly increased in mice with adipocyte-specific NT-3 overexpression, but profoundly reduced in mice with TRKC haploinsufficiency (TRKC +/−). Increasing NT-3 via pharmacological or genetic approach promotes beige adipocyte development, enhances cold-induced thermogenesis and protects against diet-induced obesity (DIO); whereas TRKC + /− or SNS TRKC deficient mice are cold intolerant and prone to DIO. Thus, NT-3 is a fat-derived neurotrophic factor that regulates SNS innervation, energy metabolism and obesity.

Plasma miR-409-3p promotes acute cerebral infarction via suppressing CTRP3.

Abnormal expression of miR-409-3p has been found in several neurodevelopmental disorders, but whether it is dysregulated in the patients with acute cerebral infarction (ACI) has not been evaluated. The current study mainly focused on the clinical significance and the underlying mechanism of plasma miR-409-3p in the progression of ACI. The level of plasma miR-409-3p was determined in ACI patients (n = 80) and healthy controls (n = 30). Pearson correlation assay was performed to evaluate the association and cardiovascular risk factors. A receiver operating characteristic curve (ROC) was used to evaluate the diagnostic value of plasma miR-409-3p levels in patients with ACI. Dual luciferase reporter assay and western blot were performed to determine the possible target gene of miR-409-3p. Our data showed that the expression of plasma miR-409-3p in the ACI group was higher than that in the healthy controls. Furthermore, Pearson correlation analysis indicated a positive correlation between plasma miR-409-3p and the NIHSS score. ROC analysis indicated that plasma miR-409-3p could differentiate plasma miR-409-3p in ACI patients from healthy controls. Then, we explored the possible target genes of miR-409-3p. Interestingly, C1q and TNF-related 3 (CTRP3), a novel adipose tissue-derived secreted factor, was found to be a target gene of miR-409-3p. We found that knockdown of CTRP3 significantly induced PC12 cell apoptosis, even in PC12 cells transfected with miR-409-3p inhibitor. These data suggested that miR-409-3p induced PC12 cell apoptosis by targeting CTRP3. Altogether, elevated plasma miR-409-3p is correlated with disease severity and may be efficient for the early diagnosis of ACI.

CTRP3 and serum triglycerides in children aged 7-10 years.

The prevalence of obesity-related disorders has been steadily increasing over the past couple of decades. Diseases that were once only detected in adults are now prevalent in children, such as hyperlipidemia. The adipose tissue-derived hormonal factor C1q TNF Related Protein 3 (CTRP3) has been linked to triglyceride regulation especially in animal models. However, the relationship between circulating CTRP3 levels and obesity-related disorders in human subjects is controversial. CTRP3 can circulate in different oligomeric complexes: trimeric (<100 kDa), middle molecular weight (100-300 kDa), and high molecular weight (HMW) oligomeric complexes (>300 kDa). Previous work has identified that it is not the total amount of CTRP3 present in the serum, but the specific circulating oligomeric complexes that appear to be indicative of the relationship between CTRP3 and serum lipids levels. However, this work has not been examined in children. Therefore, the purpose of this study was to compare the levels of different oligomeric complexes of CTRP3 and circulating lipid levels among young children (aged 7-10 years). Morphometric data and serum samples were collected and analyzed from a cross-sectional population of 62 children of self-identified Hispanic origin from a community health center, between 2015 and 2016. Serum analysis included adiponectin, insulin, leptin, ghrelin, glucagon, C-reactive peptide, triglyceride, cholesterol, IL-6, TNF, and CTRP3. Correlation analyses were conducted to explore the relationships between CTRP3 and other biomarkers. Total CTRP3 concentrations were significantly positively correlated with total cholesterol and HDL cholesterol. Whereas, HMW CTRP3 was not significantly associated with any variable measured. Conversely, the middle molecular weight (MMW) CTRP3 was negatively correlated with triglycerides levels, and very low-density lipoprotein (VLDL), insulin, and body mass index (BMI). The negative correlations between MMW CTRP3 and triglycerides and VLDLs were particularly strong (r2 = -0.826 and -0.827, respectively). Overall, these data indicate that the circulating oligomeric state of CTRP3 and not just total CTRP3 level is important for understanding the association between CTRP3 and metabolic diseases. Further, this work indicates that MMW CTRP3 plays an important role in triglyceride and VLDL regulation which requires further study.

The relationship between leptin, leptin receptor, and FGFR1 in primary human breast tumors.

e13578 Background: General/overall obesity and visceral/central obesity are associated with increased breast cancer risk and poorer cancer outcomes; however, the precise etiology of these observations is not fully known. Our previous research suggests that adipose tissue-derived fibroblast growth factor 2 (FGF2) promotes malignant transformation of mammary epithelial cells through the activation of its primary receptor, fibroblast growth factor receptor 1 (FGFR1). Both FGF2 and leptin have been shown to be elevated in the serum in obesity (body mass index (BMI) &gt; 25kg/m2). It is well established that elevated sera leptin promotes breast cancer through multiple mechanisms. Therefore, we hypothesized that tumors that express elevated FGFR1 and leptin receptor (LepR) may have a poorer prognosis in obese patients. Methods: Databases that house gene-sequenced breast cancer tumors and normal breast tissue were analyzed to discern relationships between gene copy number and mRNA levels of leptin, leptin receptor, FGFR1 and janus kinase 2 (Jak2), as Jak2 was shown to be a common downstream mediator of both FGFR1 and leptin receptor activation by Cytoscape network analysis. Furthermore, we tested the efficacy of Jak2 inhibitors for preventing mammary epithelial cell malignant transformation using our well-established models of adipose tissue-stimulated growth in soft agar. The anchorage-independent growth in soft agar is a surrogate marker for malignant transformation. Results: A much stronger significant relationship exists between FGFR1 mRNA and leptin mRNA in primary breast cancer (p = 3.17*10−9) compared with normal breast epithelium (p = 0.0013). In primary breast tumors, gene copy number of FGFR1 positively correlates with leptin copy number (p = 8.956*10−8, r = 0.19). Moreover, two separate Jak2 inhibitors attenuated both leptin+FGF2-stimulated and mouse adipose tissue-stimulated MCF-10A cell transformation. Conclusions: Taken together, these results suggest that elevated sera FGF2 and leptin in obese patients may promote breast tumorigenesis in tumors that express elevated FGFR1 and LepR and that Jak2 inhibitors may be a novel therapeutic option for adiposity-driven breast cancers. Future work will examine the relationship between FGFR1/leptin receptor expression and survival and how these relationships are influenced by BMI status.

Bone marrow adipose tissue-derived stem cell factor mediates metabolic regulation of hematopoiesis.

Hematopoiesis is dynamically regulated by metabolic cues in homeostatic and stressed conditions; however, the cellular and molecular mechanisms mediating the metabolic sensing and regulation remain largely obscure. Bone marrow adipose tissue remodels in various metabolic conditions and has been recently proposed as a niche for hematopoietic stem cells after irradiation. Here, we investigated the role of marrow adipose tissue-derived hematopoietic cytokine stem cell factor in unperturbed hematopoiesis by selectively ablating the Kitl gene from adipocytes and bone marrow stroma cells using Adipoq-Cre and Osx1-Cre, respectively. We found that both Adipoq-Kitl knockout (KO) and Osx1-Kitl KO mice diminished hematopoietic stem and progenitor cells and myeloid progenitors in the bone marrow and developed macrocytic anemia at the steady-state. The composition and differentiation of hematopoietic progenitor cells in the bone marrow dynamically responded to metabolic challenges including high fat diet, β3-adrenergic activation, thermoneutrality, and aging. However, such responses, particularly within the myeloid compartment, were largely impaired in Adipoq-Kitl KO mice. Our data demonstrate that marrow adipose tissue provides stem cell factor essentially for hematopoiesis both at the steady state and upon metabolic stresses.

143. Intracarotid Injection of Adipose Tissue-Derived Platelet-Derived Growth Factor Receptor γ-Positive Cells in Rat and Canine Model: Feasibility of Cell Delivery under Mannitol-Induced Blood-Brain Barrier Opening

143. Intracarotid Injection of Adipose Tissue-Derived Platelet-Derived Growth Factor Receptor γ-Positive Cells in Rat and Canine Model: Feasibility of Cell Delivery under Mannitol-Induced Blood-Brain Barrier Opening

Adiponectin Attenuates Lipopolysaccharide-Induced Acute Lung Injury through Suppression of Endothelial Cell Activation

Adiponectin (APN) is an adipose tissue-derived factor with anti-inflammatory and vascular protective properties whose levels paradoxically decrease with increasing body fat. In this study, APN's role in the early development of ALI to LPS was investigated. Intratracheal LPS elicited an exaggerated systemic inflammatory response in APN-deficient (APN(-/-)) mice compared with wild-type (wt) littermates. Increased lung injury and inflammation were observed in APN(-/-) mice as early as 4 h after delivery of LPS. Targeted gene expression profiling performed on immune and endothelial cells isolated from lung digests 4 h after LPS administration showed increased proinflammatory gene expression (e.g., IL-6) only in endothelial cells of APN(-/-) mice when compared with wt mice. Direct effects on lung endothelium were demonstrated by APN's ability to inhibit LPS-induced IL-6 production in primary human endothelial cells in culture. Furthermore, T-cadherin-deficient mice that have significantly reduced lung airspace APN but high serum APN levels had pulmonary inflammatory responses after intratracheal LPS that were similar to those of wt mice. These findings indicate the importance of serum APN in modulating LPS-induced ALI and suggest that conditions leading to hypoadiponectinemia (e.g., obesity) predispose to development of ALI through exaggerated inflammatory response in pulmonary vascular endothelium.

Adiponectin plays a protective role in caerulein-induced acute pancreatitis in mice fed a high-fat diet

Background:Obesity is a risk factor for acute pancreatitis (AP), but the molecular mechanism remains unclear. Adiponectin, an adipose tissue-derived secretory factor, has anti-inflammatory properties in addition to various biological functions,...

Adiposity-Related Protection of Intestinal Tumorigenesis: Interaction With Dietary Calcium

Although high-calcium diets have been reported to reduce the risk of colorectal cancer, our preliminary data with the adenomatous polyposis coli (Apc) Min mutation (Min/+;ApcMin/+) mouse shows a paradoxical increase in intestinal tumor loads (> 65%) with high calcium diets. Since we previously demonstrated that increasing dietary calcium reduces adiposity, and ApcMin/+ mice on high calcium diets exhibited profound loss of adipose tissue, we hypothesized that loss of an adipose tissue-derived tumor suppressor factor(s) resulted in increased tumor susceptibility in animals on the high calcium diet. Accordingly, tumor prone ApcMin/+ mice were crossed with obesity prone lethal yellow agouti (A y /a) mice to generate obese Ay/ApcMin/+ mice. Low (0.2%), normal (0.5%), and high (1.2%) calcium diets were fed to both Ay/Apc Min/+ mice and ApcMin/+ mice from 35–40 days until 90 days of age (n = 21/strain, n = 7/diet group). The high calcium diet reduced weight gain in both strains (P < 0.01) and reduced fat pad mass by 46–57% in A y /ApcMin/+(P < 0.004) and by 65–82% in ApcMin/+(P < 0.03).ApcMin/+ mice on the high calcium diet exhibited an increase in tumor number (76 vs. 29, P = 0.009), but this effect was not seen in the Ay/ApcMin/+ mice.β-Catenin and cyclin D1 gene expression were significantly induced with high calcium diet in intestinal tumor tissue of ApcMin/+ mice but not in Ay/ApcMin/+ mice. We conclude that the differential effect of dietary calcium on intestinal tumorigenesis in lean vs. obese ApcMin/+ may result from the loss of adipose-derived protective factor(s) due to the substantial loss of body fat in ApcMin/+ mice fed a high calcium dairy diet, increasingβ-catenin and cyclin D1 in tumors.

Resistin and RELM-α gene expression in white adipose tissue of lactating mice

The adipose tissue-derived factor resistin has been suggested to induce insulin resistance in obesity and inhibit adipocyte differentiation. Lactation is associated with major metabolic adaptations, which cause a profound loss of adipose tissue to support milk production by the mammary gland. This study has examined the expression of the resistin and resistin-like molecule-α (RELM-α) genes in white adipose tissue of lactating mice. Lactation induced significant increases in food intake and body weight, whereas body fat was substantially decreased at peak lactation. Resistin and RELM-α mRNAs were both detectable in gonadal, subcutaneous, and mammary gland fat; mRNA level was highest in gonadal fat and lowest in mammary tissue. There was no difference in resistin mRNA level in gonadal fat of lactating mice compared with controls. However, RELM-α mRNA fell by approximately 40% in early lactation and there was a parallel fall in the leptin mRNA level proportional to the loss of fat mass. These results indicate that the substantial reduction of adiposity in lactation does not lead to any changes in resistin gene expression; however, the fall in RELM-α mRNA might indicate a role for RELM-α in the metabolic adaptations of lactation.

Decreased 5-HT transporter mRNA in neurons of the dorsal raphe nucleus and behavioral depression in the obese leptin-deficient ob/ob mouse

The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) is an important regulator of feeding behavior. A hypothalamic site of action for 5-HT in body weight control is supported by the presence of 5-HT receptors in hypothalamic regions which are intimately associated with regulation of food intake. In the present study we have investigated whether there may be an interaction between the hormone leptin, an adipose tissue-derived cytokine signaling factor that inhibits food intake and lowers body weight, and the brain serotonergic system. Immunohistochemical analysis of colchicine-treated rats showed colocalization of 5-HT transporter- and leptin receptor-immunoreactivity in cell bodies of the dorsal raphe nucleus, suggesting that dorsal raphe neurons are targets for circulating leptin. Levels of 5-HT transporter mRNA expression were compared in neurons of the dorsal raphe nucleus of obese leptin-deficient ob/ob mice and their lean littermates using in situ hybridization. 5-HT transporter mRNA levels were significantly down-regulated in neurons of the dorsal raphe nucleus of obese ob/ob mice as compared to lean control mice. Behavioral analysis showed that obese ob/ob mice had significantly lower locomotor activity and exhibited increased immobility in Porsolt’s test, a model for depression. Taken together, these results suggest that serotonergic cell bodies in the rodent dorsal raphe nucleus possess leptin receptors and that the serotonergic system, as reflected by expression levels of 5-HT transporter mRNA, is down-regulated in the obese behaviorally depressed ob/ob mouse.

Alteration of the leptin network in late morbid obesity induced in mice by brain infection with canine distemper virus.

Viruses can induce progressive neurologic disorders associated with diverse pathological manifestations, and therefore, viral infection of the brain can impair differentiated neural functions, depending on the initial viral tropism. We have previously reported that canine distemper virus (CDV) targets certain mouse brain structures, including the hypothalamus, early and selectively. Infected mice exhibit acute encephalitis, with late disease, characterized by motor impairment or obesity syndrome, appearing in some of the surviving mice several months after the initial viral replication. In the present study, we show viral persistence in the hypothalami of obese mice, as demonstrated by low, but still significant, levels of CDV nucleoprotein transcripts, associated with a dramatic decrease in F gene mRNAs. Given the pivotal role of the hypothalamus in obesity (eating behavior, energy consumption, and neuroendocrine function) and that of leptin, the adipose tissue-derived satiety factor acting through hypothalamic receptors, we analyzed the leptin networks in both obese and nonobese mice. The discrepancy found between the chronic and dramatic increase in blood leptin levels and the occurrence of obesity may be due to leptin resistance in the brain. In fact, expression of the long leptin receptor isoform, representing the functional leptin receptor, was specifically downregulated in the hypothalami of obese mice, explaining their inability to generate an adequate response to leptin in the brain. Intriguingly, during the acute phase of infection, its expression was increased in CDV-targeted structures in all infected mice and remained high in obese mice in all CDV-targeted structures, except for the hypothalamus. The biphasic change in hypothalamic leptin receptor expression seen during the progression of CDV-induced obesity provides a new paradigm for understanding mechanisms of neuroendocrinological, virus-induced abnormalities.

Leptin Directly Stimulates Catecholamine Secretion and Synthesis in Cultured Porcine Adrenal Medullary Chromaffin Cells

Leptin, a protein encoded by the ob gene, is an adipose tissue-derived signaling factor involved in body weight homeostasis. The hypothalamus is a major site of central action for leptin. However, mounting evidence indicates expression of leptin receptor mRNA in various peripheral organs including the adrenal medulla. Therefore, we investigated the effects of leptin on catecholamine secretion and synthesis in cultured porcine adrenal medullary chromaffin cells. We initially confirmed the expression of leptin receptor (Ob-Rb) mRNA in cultured porcine adrenal medullary cells. Murine recombinant leptin (≧50 nM) strongly induced the release of both epinephrine (E) and norepinephrine (NE) from chromaffin cells. Removal of external Ca2+ significantly suppressed these effects. Also, leptin (≧1 nM) enhanced nicotine-induced increases in E- and NE. Leptin (1, 10, 100 nM) significantly increased tyrosine hydroxylase (TH) (a rate-limiting enzyme in the biosynthesis of catecholamine) mRNA levels in a concentration-dependent manner. Furthermore, leptin (1, 10, 100 nM) significantly induced increases in cAMP levels, suggesting that the stimulatory effects on TH mRNA are mediated, at least in part, by the cAMP/protein kinase A pathway. These results indicate that leptin directly stimulates catecholamine release and synthesis, which in turn may potentiate the anti-obesity effects of leptin.

Adipose tissue-derived tumor necrosis factor activity correlates with fat cell size but not insulin action in aging rats.

Adipose tissue-derived tumor necrosis factor (AT-TNF) protein and messenger RNA (mRNA) has been shown to correlate with insulin resistance in some studies. However, in a study using different aged Fischer 344 rats, AT-TNF activity correlated more strongly with cell size than with fasting plasma insulin. The present study was undertaken to more carefully examine the relationship among AT-TNF, adipose cell size, and insulin action using more precise measures of insulin action. Basal and hyperinsulinemic, euglycemic clamps were performed in male Sprague Dawley rats at four different ages (8, 13, 21, and 61 weeks old). [3-(3)H]glucose and 2-deoxy-D-[1-(14)C]glucose were used to assess glucose kinetics and tissue-specific glucose uptake. Because TNF activity represents the summation of TNF synthesis, secretion, and the amount of soluble inhibitors present, TNF activity was measured using a bioassay, in addition to measuring TNF protein and mRNA levels. AT-TNF activity increased significantly with age, as did the glucose infusion rate, a measure of whole body insulin resistance. However, AT-TNF activity did not correlate with any parameter of insulin action measured during the hyperinsulinemic, euglycemic clamps. In epididymal fat, AT-TNF activity correlated with: glucose infusion rate: r = -0.50, P = 0.17; rate of appearance: r = -0.19, P = 0.35; rate of disappearance: r = 0.08, P = 0.69. As was noted before, AT-TNF activity correlated well with fat cell size (r = 0.76, P < 0.001 in epididymal fat; r = 0.58, P = 0.007 in SUB fat). These data suggest that although AT-TNF activity and insulin resistance increase with age, the two are not functionally related. These data do not eliminate the potential role of nonadipose TNF in the regulation of insulin action.

Adipose Tissue-Derived Tumor Necrosis Factor Activity Correlates with Fat Cell Size But Not Insulin Action in Aging Rats

Adipose Tissue-Derived Tumor Necrosis Factor Activity Correlates with Fat Cell Size But Not Insulin Action in Aging Rats

Leptin levels in pregnancy, marker for fat accumulation and mobilization?

Leptin, an adipose tissue-derived signalling factor encoded by the obese gene has been shown to be present as a 16-kDa protein in the blood of mice and humans. Resistance to leptin occurs in human obesity. Leptin has also been shown to associate with plasma insulin concentrations and there is currently considerable debate about the potential link between insulin resistance and resistance to leptin. In non-pregnant individuals, circulating leptin concentrations associate strongly with both total body fat mass and body mass index (BMI). In normal human pregnancy, the maternal fat stores increase to a peak in the late second trimester, before declining towards term as fat stores are mobilized to support the rapidly growing fetus. Insulin resistance increases during late pregnancy and is believed to be further enhanced in pregnancies complicated by pre-eclampsia. The aim of this study was to examine if leptin levels were altered in pregnancy and, if so, whether the pattern of change in circulating leptin related to previously established changes in fasting insulin concentrations or fat mass. We measured third trimester plasma leptin concentrations in 12 uncomplicated pregnant women, nine women with pre-eclampsia matched for age and booking BMI, and 18 non-pregnant women similarly matched. We also examined the longitudinal course of leptin concentrations occurring throughout gestation (from 10 weeks gestation and at five week intervals thereafter), in five normal pregnancies and two women with gestational-onset diabetes. Leptin concentrations were significantly higher in the normal pregnant women (37.1 microg/L, [15.4-117.0], geometric mean, [range]; p=0.049), and women with pre-eclampsia (45.3 microg/L, [21.3-98.4]; p=0.001), than in non-pregnant controls (17.85 microg/L, [1.3-36.5]), however, there was no significant difference between uncomplicated and pre-eclamptic pregnancies (p=0.22). On examination of the longitudinal course of leptin concentrations occurring throughout gestation, in all seven women plasma leptin concentrations initially increased relative to booking (10 weeks) concentrations, but did so by varying amounts (ranging between 30-233%). Significantly, however, in all seven women plasma leptin concentrations peaked at around 20-30 weeks of gestation before declining towards term. On the basis of these observations, we postulate that plasma leptin levels increase significantly in human pregnancies and that the pattern of change in circulating leptin parallels the process of fat accumulation and mobilization.