|
|
|
多肽/蛋白质生物标志物和糖尿病治疗
| |
脂肪组织中的多肽/蛋白质对葡萄糖动态平衡的影响 |
 |
All homeotherms use thermogenesis to maintain their core body temperature, ensuring that cellular functions and physiological processes can continue in cold environments. In the prevailing model of thermogenesis, when the hypothalamus senses cold temperatures it triggers sympathetic discharge, resulting in the release of noradrenaline in brown adipose tissue and white adipose tissue. Acting via the β(3)-adrenergic receptors, noradrenaline induces lipolysis in white adipocytes, whereas it stimulates the expression of thermogenic genes, such as PPAR-γ coactivator 1a (Ppargc1a), uncoupling protein 1 (Ucp1) and acyl-CoA synthetase long-chain family member 1 (Acsl1), in brown adipocytes. However, the precise nature of all the cell types involved in this efferent loop is not well established. Here we report in mice an unexpected requirement for the interleukin-4 (IL-4)-stimulated program of alternative macrophage activation in adaptive thermogenesis. Exposure to cold temperature rapidly promoted alternative activation of adipose tissue macrophages, which secrete catecholamines to induce thermogenic gene expression in brown adipose tissue and lipolysis in white adipose tissue. Absence of alternatively activated macrophages impaired metabolic adaptations to cold, whereas administration of IL-4 increased thermogenic gene expression, fatty acid mobilization and energy expenditure, all in a macrophage-dependent manner. Thus, we have discovered a role for alternatively activated macrophages in the orchestration of an important mammalian stress response, the response to cold.
Nguyen KD, Qiu Y, Cui X et al, Nature. 2011 Nov 20;480(7375):104-8. doi: 10.1038/nature10653
|
|
Glucagon-like peptide 1 (GLP-1), a gut-derived peptide, has been reported to have profound effects on metabolism and to reduce insulin resistance. Adipocyte hyperplasia stimulated by preadipocyte differentiation has a positive effect on adipose tissue insulin sensitivity. However, it remains less clear whether GLP-1 plays a role in adipogenesis. In this study, we examined the effect of GLP-1 on preadipocyte differentiation and investigated the mechanisms that may be involved in this effect. In our 3T3-L1 cell study, we tested the levels of adipocyte-specific markers and signaling pathways during preadipocyte differentiation. In addition, Oil Red O staining was used to examine lipid accumulation. Image Pro Plus 5.02 was used to analyze the size and number of lipid droplets. We found that GLP-1 elevated the protein expression levels of free fatty acid binding protein 4 (aP2) and the transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ) in a dose-dependent manner during 3T3-L1 preadipocyte differentiation. Furthermore, RT-PCR results showed that GLP-1 promoted CCAAT/enhancer-binding protein α (C/EBPα) and lipoprotein lipase (LPL) expression at the transcriptional level. These data suggest that GLP-1 promotes preadipocyte differentiation. Our study also found that treatment of the cells with 100 nM GLP-1 enhanced the phosphorylation of Akt signaling during the first 24h of differentiation. Although Oil Red O staining showed that GLP-1 had no significant effect on lipid accumulation, there were increased numbers of small adipocytes in the cells treated with 100 nM GLP-1. Taken together, these results indicate that GLP-1 regulates 3T3-L1 adipogenesis and the Akt signaling pathway may be involved in this process. The differentiated small adipocytes may have a positive effect against insulin resistance and obesity.
Yang J, Ren J, Song J et al, Int J Mol Med. 2013 Jun;31(6):1429-35. doi: 10.3892/ijmm.2013.1350. Epub 2013 Apr 15.
|
|
The novel satiety factor nesfatin-1 and its precursor NUCB2 are widely expressed neuropeptides in the central nervous system. Nesfatin-1/NUCB2 is also localized in peripheral tissues and regulates the glucose and energy metabolism at multiple processes. Nesfatin-1 potentiates both insulin release from pancreatic β-cells and insulin action in liver, contributing to energy storage. Furthermore, nesfatin-1/NUCB2 regulates adipocyte differentiation. The polymorphism of the NUCB2 gene is associated with obesity. Thus, nesfatin-1/NUCB2 plays a role in integrating feeding, glucose homeostasis, and energy storage/expenditure. Dysfunction of expression, secretion and/or action of nesfatin-1/NUCB2 might be involved in the type 2 diabetes, obesity and metabolic syndrome. Nesfatin-1/NUCB2 and its regulatory processes may provide novel targets for treating associated diseases of the metabolic syndrome. Here we review the published studies so far on nesfatin-1/NUCB2 localization and action in islets and discuss the physiological and pathophysiological roles of the nesfatin-1/NUCB2 in glucose and energy metabolism.
Nakata M, Yada T. Curr Pharm Des. 2013 Mar 25. [Epub ahead of print]
|
|
CONTEXT:
Cold exposure stimulates fibroblast growth factor 21 (FGF21) secretion in animals, enhancing the cold-induced thermogenesis (CIT) response through browning of white adipose tissue. In humans, the effects of cold exposure on circulating FGF21 levels are unknown.
OBJECTIVE:
Our objective was to evaluate the effects of mild cold exposure on circulating FGF21 and its relationship with CIT and lipolysis in humans.
DESIGN AND SETTING:
We conducted a randomized, single-blind, crossover intervention study at the National Institutes of Health Clinical Center.
PARTICIPANTS:
Participants were healthy adults. Intervention: Subjects were exposed to a 12-h exposure to 24 or 19 C in a whole-room indirect calorimeter.
OUTCOME MEASURES:
Energy expenditure, plasma FGF 21, nonesterified fatty acid, and adipose tissue microdialysis glycerol concentrations were evaluated.
RESULTS:
At 24 C, plasma FGF21 exhibited a diurnal rhythm, peaking at 0800 h [110 (59-178) pg/ml], and progressively dropped to a nadir at 1700 h [41 (21-71) pg/ml, P < 0.0001] before rising at 1900 h [60 (11-81) pg/ml, P < 0.0001]. Exposure at 19 C lessened the diurnal reduction of FGF21 observed at 24 C from 0800-1700 h and augmented overall FGF21 levels by 37 ± 45% (P = 0.01). The change in area under the curve plasma FGF21 between 19 and 24 C correlated positively with the change in area under the curve adipose microdialysate glycerol (R(2) = 0.35, P = 0.04) but not with nonesterified fatty acid. Cold-induced increase in FGF21 predicted greater rise in energy expenditure during cold exposure (β = 0.66, P = 0.027), independent of age, gender, fat mass, and lean mass.
CONCLUSIONS:
Mild cold exposure increased circulating FGF21 levels, predicting greater lipolysis and CIT. A small reduction in environmental temperature is sufficient to modulate FGF21 diurnal rhythm in humans, which may mediate cold-induced metabolic changes similar to those in animals.
Lee P et al, J Clin Endocrinol Metab. 2013 Jan;98(1):E98-102. doi: 10.1210/jc.2012-3107. Epub 2012 Nov 12.
|
|
The ability of mammals to resist body fat accumulation is linked to their ability to expand the number and activity of "brown adipocytes" within white fat depots. Activation of β-adrenergic receptors (β-ARs) can induce a functional "brown-like" adipocyte phenotype. As cardiac natriuretic peptides (NPs) and β-AR agonists are similarly potent at stimulating lipolysis in human adipocytes, we investigated whether NPs could induce human and mouse adipocytes to acquire brown adipocyte features, including a capacity for thermogenic energy expenditure mediated by uncoupling protein 1 (UCP1). In human adipocytes, atrial NP (ANP) and ventricular NP (BNP) activated PPARγ coactivator-1α (PGC-1α) and UCP1 expression, induced mitochondriogenesis, and increased uncoupled and total respiration. At low concentrations, ANP and β-AR agonists additively enhanced expression of brown fat and mitochondrial markers in a p38 MAPK-dependent manner. Mice exposed to cold temperatures had increased levels of circulating NPs as well as higher expression of NP signaling receptor and lower expression of the NP clearance receptor (Nprc) in brown adipose tissue (BAT) and white adipose tissue (WAT). NPR-C(-/-) mice had markedly smaller WAT and BAT depots but higher expression of thermogenic genes such as Ucp1. Infusion of BNP into mice robustly increased Ucp1 and Pgc-1α expression in WAT and BAT, with corresponding elevation of respiration and energy expenditure. These results suggest that NPs promote "browning" of white adipocytes to increase energy expenditure, defining the heart as a central regulator of adipose tissue biology.
Bordicchia M, Liu D, Amri EZ et al, J Clin Invest. 2012 Mar 1;122(3):1022-36. doi: 10.1172/JCI59701. Epub 2012 Feb 6.
|
|
AIMSHYPOTHESIS:
The excessive accumulation of adipose tissue in the obese state is linked to an altered secretion profile of adipocytes, chronic low-grade inflammation and metabolic complications. RBP4 has been implicated in these alterations, especially insulin resistance. The aim of the present study was to determine if a local inflammatory micro-environment in adipose tissue regulates RBP4 expression and secretion.
METHODS:
Human SGBS and primary adipocytes cultured with conditioned media from human THP-1 macrophages were used as an in vitro model for adipose inflammation. Adipocytes were exposed to recombinant TNF-α, IL-1β, IL-6 or IL-8. In addition, coexpression of IL-1β and RBP4 was measured in adipose tissue samples from 18 healthy females. RBP4 expression was studied by quantitative PCR and ELISA.
RESULTS:
RBP4 mRNA expression and secretion was significantly reduced upon incubation with macrophage-conditioned media in SGBS adipocytes and human primary adipocytes. Out of several factors studied we identified IL-1β as a new factor regulating RBP4. IL-1β significantly downregulated RBP4 mRNA and secretion in a time- and dose-dependent manner. IL-1β mediated its inhibitory effects on RBP4 expression via IL-1 receptor and NF-κB, as incubation with the IL-1 receptor blocking antibody and the NF-κB inhibitors CAPE and SC-514 reversed its effect. Most interestingly, RBP4 mRNA was negatively correlated with IL-1β mRNA in subcutaneous adipose tissue.
CONCLUSIONS:
Adipose tissue inflammation as found in the obese state might lead to a downregulation in local RBP4 levels. IL-1β was identified as a major factor contributing to the decrease in RBP4. The increase in circulating RBP4 that often precedes the development of systemic insulin resistance is most likely unrelated to inflammatory processes in adipose tissue.
Kotnik P et al, PLoS One. 2013;8(2):e57796. doi: 10.1371/journal.pone.0057796. Epub 2013 Feb 27.
|
|
OBJECTIVE:
The melanocortin system has a highly significant role in the hypothalamic regulation of body weight and energy expenditure. In animals, intracerebroventricular infusion of melanocortin receptor 4 (MCR-4) agonists increases basal metabolic rate through activation of the sympathetic nervous system and subsequently reduces food intake. In humans, direct access of MCR-4 agonists to the central nervous system can be achieved by a transnasal route, which leads to weight loss with chronic administration. In the present study, we aimed at investigating the effects of intranasally administered MC4-R agonist MSH/ACTH (4-10) on lipolysis and sympathetic nervous system activity in healthy humans.
DESIGN:
Healthy normal weight, male volunteers (n=10) received either 10 mg MSH/ACTH (4-10) or placebo intranasally in a double-blinded randomized crossover design. Interstitial glycerol release was assessed by microdialysis in abdominal white adipose tissue (WAT) and in skeletal muscle (SM) of the forearm. Local blood flow, systemic blood pressure, heart rate and muscle sympathetic nerve activity (MSNA) within the superficial peroneal nerve were recorded at rest and after nitroprusside infusion.
RESULTS:
At 45 min after MSH/ACTH (4-10) administration WAT glycerol concentrations increased by 53.4 ± 19.3% compared with baseline conditions (P<0.05) and remained significantly higher throughout the experiment when compared with placebo (P<0.05) while local glycerol release in SM was not significantly affected. Resting MSNA was not altered by MSH/ACTH (4-10) administration; however, sympathoexcitation by intravenous nitroprusside was markedly elevated (MSH/ACTH (4-10) 569 ± 69% increase to baseline; placebo: 315 ± 64%; P<0.01).
CONCLUSION:
Intranasally administered MCR-4 agonist MSH/ACTH 4-10 increases both subcutaneous WAT lipolysis and MSNA, which suggests a direct central nervous peptide effect in humans on key factors of human energy metabolism.
Wellhöner P Int J Obes (Lond). 2012 May;36(5):703-8. doi: 10.1038/ijo.2011.105. Epub 2011 May 31.
|
|
Chromogranin A knock-out (Chga-KO) mice display increased adiposity despite high levels of circulating catecholamines and leptin. Consistent with diet-induced obese mice, desensitization of leptin receptors caused by hyperleptinemia is believed to contribute to the obese phenotype of these KO mice. In contrast, obesity in ob/ob mice is caused by leptin deficiency. To characterize the metabolic phenotype, Chga-KO mice were treated with the CHGA-derived peptide catestatin (CST) (Phoenix’s Catalog # 053-28) that is deficient in these mice. CST treatment reduced fat depot size and increased lipolysis and fatty acid oxidation. In liver, CST enhanced oxidation of fatty acids as well as their assimilation into lipids, effects that are attributable to the up-regulation of genes promoting fatty acid oxidation (Cpt1α, Pparα, Acox, and Ucp2) and incorporation into lipids (Gpat and CD36). CST did not affect basal or isoproterenol-stimulated cAMP production in adipocytes but inhibited phospholipase C activation by the α-adrenergic receptor (AR) agonist phenylephrine, suggesting inhibition of α-AR signaling by CST. Indeed, CST mimicked the lipolytic effect of the α-AR blocker phentolamine on adipocytes. Moreover, CST reversed the hyperleptinemia of Chga-KO mice and improved leptin signaling as determined by phosphorylation of AMPK and Stat3. CST also improved peripheral leptin sensitivity in diet-induced obese mice. In ob/ob mice, CST enhanced leptin-induced signaling in adipose tissue. In conclusion, our results implicate CST in a novel pathway that promotes lipolysis and fatty acid oxidation by blocking α-AR signaling as well as by enhancing leptin receptor signaling.
Bandyopadhyay GK, Vu CU, Gentile S et al, J Biol Chem. 2012 Jun 29;287(27):23141-51. doi: 10.1074/jbc.M111.335877. Epub 2012 Apr 25.
|
|
BRS-3 KO-mice developed obesity and unbalanced glucose metabolism, suggesting an important role of BRS-3 receptor in glucose homeostasis. We explored BRS-3 expression in skeletal muscle from normal, obese or type-2 diabetic (T2D) patients, and the effect of [D-Phe(6), β-Ala(11),Phe(13),Nle(14)]bombesin(6-14)-BRS-3-agonist-peptide (BRS-3-AP) (Phoenix’s Catalog # 007-10)- on glucose-related effects, before or after BRS-3 gene silencing. In muscle tissue and primary cultured myocytes from altered metabolic states, BRS-3 gene/protein expressions were down-regulated. In normal, obese and T2D cells: A) BRS-3-AP as insulin enhanced BRS-3 and GLUT-4 mRNA/protein levels; improving glucotransporter translocation to plasma membrane, and B) BRS-3-AP caused a concentration-related-stimulation of glucose transport, being obese and T2D myocytes more sensitive to the ligand than normal. Wortmannin and PD98059, but not rapamycin, abolished the stimulatory action of BRS-3-AP on glucose transport. BRS-3 plays an important role in glucose metabolism, and could be use as a molecular target, and/or its ligand, as a therapeutic agent for obesity and diabetes treatments.
Ramos-¨¢lvarez I, Mart¨ªn-Duce A, Moreno-Villegas Z et al, Mol Cell Endocrinol. 2013 Mar 10;367(1-2):109-15. doi: 10.1016/j.mce.2012.12.025. Epub 2013 Jan 3.
|
|
Neuropeptide Y (NPY) is expressed in adipose tissue and is involved in adipocyte metabolism. Although NPY impacts on glucose utilization in vivo, the underlying cellular mechanism is yet to be fully elucidated. In this study we investigated the effect of NPY on the insulin-stimulated translocation of glucose transporter 4 (GLUT4) from intracellular stores to the cell surface in vitro. Using cellular fractionation and immunofluorescence we analyzed the cellular localization and content of GLUT4 in 3T3-L1 adipocytes. Additionally we investigated the effect of NPY on insulin action in adipocyte cultures by assessing the phosphorylation of Akt and [(3)H]-deoxyglucose uptake. Our data suggest that in 3T3-L1 adipocytes NPY inhibits insulin-stimulated glucose uptake in a GLUT4-dependent manner. The insulin induced translocation of GLUT4 was attenuated by the Y1 receptor agonist [Phe(7),Pro(34)] pNPY, demonstrating an essential role of the Y1 receptor in GLUT4 translocation. Additionally, we observed an NPY dose-dependent impairment of Akt phosphorylation. This study provides evidence that NPY impairs the insulin sensitivity of adipocytes and suggests that the Y1 receptor could be a potential therapeutic target for type 2 diabetes.
Gericke MT et al, Mol Cell Endocrinol. 2012 Jan 2;348(1):27-32. doi: 10.1016/j.mce.2011.07.028. Epub 2011 Jul 27.
|
|
Cocaine- and amphetamine-regulated transcript (CART) is a regulatory peptide expressed in the nervous system and in endocrine cells, e.g. in pancreatic islets. CART deficient mice exhibit islet dysfunction, impaired insulin secretion and increased body weight. A mutation in the CART gene in humans is associated with reduced metabolic rate, obesity and diabetes. Furthermore, CART is upregulated in islets of type-2 diabetic rats and regulates islet hormone secretion in vitro. While the function of CART in the nervous system has been extensively studied, there is no information on its expression or function in white adipose tissue. CART mRNA and protein were found to be expressed in both subcutaneous and visceral white adipose tissue from rat and man. Stimulating rat primary adipocytes with CART significantly potentiated isoprenaline-induced lipolysis, and hormone sensitive lipase activation (phosphorylation of Ser 563). On the other hand, CART significantly potentiated the inhibitory effect of insulin on isoprenaline-induced lipolysis. CART inhibited insulin-induced glucose uptake and lipogenesis, which was associated with inhibition of PKB phosphorylation. In conclusion, CART is a novel constituent of human and rat adipocytes and affects several biological processes central in both lipid- and glucose homeostasis. Depending on the surrounding conditions, the effects of CART are insulin-like or insulin-antagonistic.
Banke E et al, BiochimRegul Pept. 2013 Mar 10;182:35-40. doi: 10.1016/j.regpep.2012.12.011. Epub 2013 Jan 11.
|
|
Angiotensin II (AngII), a peptide hormone released by adipocytes, can be catabolized by adipose angiotensin-converting enzyme 2 (ACE2) to form Ang(1-7). Co-expression of AngII receptors (AT1 and AT2) and Ang(1-7) receptors (Mas) in adipocytes implies the autocrine regulation of local angiotensin system on adipocyte functions, through yet unknown interactive mechanisms. In the present study, we reveal the adipogenic effects of Ang(1-7) through activation of Mas receptor and its subtle interplays with the anti-adipogenic AngII-AT1 signaling pathways. Specifically, in human and 3T3-L1 pre-adipocytes, Ang(1-7)-Mas signaling promotes adipogenesis via activation of PI3 kinase/Akt and inhibition of MAPK kinase/ERK pathways. And Ang(1-7)-Mas antagonizes the anti-adipogenic effect of AngII-AT1 by inhibiting AngII-AT1 triggered MAPK kinase/ERK pathway. The autocrine regulation of AngII/AT1 - ACE2 - Ang(1-7)/Mas axis on adipogenesis has also been revealed. This study suggests the importance of the local regulations of the delicately-balanced angiotensin system on adipogenesis, and its potential as a novel therapeutic target for obesity and related metabolic disorders.
Than A et al, J Biol Chem. 2013 Apr 16. [Epub ahead of print]
|
|
RFamide neuropeptides NPFF and NPAF affect gene expression in mature 3T3-L1 adipocytes but their role on adipogenesis is unknown. Here, we show that NPFF, NPAF, and NPSF inhibited the differentiation of 3T3-F442A preadipocytes in a concentration-dependent manner, but had no effect on 3T3-L1 adipogenesis. All three neuropeptides also blocked the adipose differentiation of normal and lipoma-derived human preadipocytes. The antiadipogenic effect of RFamide neuropeptides was linked with the overexpression of Id3 gene and the inhibition by NPAF remained after neuropeptide removal and further incubation of 3T3 cells with adipogenic medium. Our results show that NPFF, NPAF and NPSF negatively affect adipogenesis and suggest that these compounds participate in the regulation of the adipose tissue development by the central nervous system.
Herrera-Herrera ML, Salazar-Olivo LA. Biochem Biophys Res Commun. 2008 Dec 5;377(1):29-34. doi: 10.1016/j.bbrc.2008.09.071. Epub 2008 Sep 25.
|
|
Ghrelin and obestatin are encoded by the preproghrelin gene and originate from post-translational processing of the preproghrelin peptide. Obestatin is mainly present in the stomach, but its action is focused on appetite inhibition in opposition to ghrelin function. Recently, it has been presented that obestatin may regulate adipocyte metabolism and influence fat content. However, obestatin action is still poorly understood. Therefore, we aimed to investigate obestatin function on adipocyte metabolism in the rat. We studied changes in the mRNA expression of active and inactive isoforms of obestatin receptors. In addition, we analyzed influence of obestatin on lipogenesis, lipolysis and glucose transport in isolated adipocytes. Moreover, we also performed analysis of obestatin action on lipolysis in differentiated rat preadipocytes with silenced obestatin receptor. We found significantly higher expression of the obestatin receptor Gpr39-1a active form at an mRNA level following adipocytes incubation with obestatin. We did not observe expression changes in the inactive form of obestatin receptor Gpr39-1b. Additionally, we found significant changes in Gpr39-1a expression following obestatin receptor silencing in cells incubated with obestatin in comparison to control. Obestatin inhibited both, basal and insulin-stimulated lipogenesis and glucose transport in adipocytes. Furthermore, obestatin potentiated adrenalin-stimulated lipolysis. We also found reduced glycerol release following obestatin incubation in adipocytes with silenced Gpr39 gene. Our results indicate that obestatin acts via the GPR39 receptor in isolated adipocytes, and that through this mechanism obestatin influences lipid accumulation, glucose uptake and lipolysis.
Pruszynska-Oszmalek E et al, J Biol Regul Homeost Agents. 2013 Jan-Mar;27(1):23-33.
|
|
The neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are structurally and functionally related. Their actions have been shown to be mediated by three different receptor subtypes: PAC1-R, which has exclusive affinity for PACAP, and VPAC1-R and VPAC2-R, which have equal affinity for PACAP and VIP. We recently showed that PACAP38 induces lipolysis in rat adipocytes, and in the present study we examined whether VIP has similar effects and which of the three receptors mediates this PACAP/VIP action. We showed by RT-PCR that all three receptor subtypes are present in rat adipocytes. We demonstrated that VIP (1-100 nm), like PACAP38, stimulates lipolysis in isolated adipocytes, as determined by glycerol release. By a pharmacological approach, using antagonists and agonists specific for the receptor subtypes, we elucidated the mechanisms by which PACAP38 and VIP mediate their lipolytic effects. We found that antagonists of PAC1-R [PACAP(6-38)] and VPAC1-R (PG97-269) did not affect lipolysis induced by 0.1-100 nm PACAP38 or VIP, and that a VPAC1-R agonist [K15, R16, L27VIP(1-7)GRF(8-27)] did not affect lipolysis at 1-1000 nm. However, two different VPAC2-R agonists [Hexa-VIP(1-28) and Ro25-1553] clearly mimicked the lipolytic effect of PACAP38 and VIP. In addition, the VPAC2-R antagonist PG99-465 (100 nm) caused right-shifted dose-response curves of PACAP38- and VIP-induced lipolysis. These results therefore provide evidence that all three PACAP/VIP receptor subtypes are expressed in primary rat adipocytes, but that the VPAC2-R subtype is responsible for mediating the lipolytic effects induced by PACAP38 and VIP.
Akesson L et al, Endocrinology. 2005 Feb;146(2):744-50. Epub 2004 Oct 28.
|
|
Somatostatin (SRIF) is a well-known neuroendocrine secretion product. SRIF expression and secretion are induced after inflammation in murine macrophages and in endotoxin-injected sheep and pigs. Because adipocytes have been demonstrated to produce numerous cytokines and peptide hormones, we investigated the expression of SRIF and its receptors (SSTR1-5) in human adipose tissue after inflammatory stimulation in vitro and in tissues from patients with septic disease.Preadipocyte-derived adipocytes, mesenchymal stem cell-derived adipocytes, and mature explanted adipocytes expressed SRIF-mRNA after endotoxin [lipopolysaccharide (LPS)] or IL-1beta treatments. LPS- and IL-1beta-mediated SRIF-mRNA induction was blocked by pretreatment with dexamethasone. Using cocultures and quantitative real-time PCR, we demonstrate adipocyte SRIF induction by secretion factors from activated peripheral blood mononuclear cell-derived macrophages. In contrast to basal adipocytes, SRIF protein was detected in culture supernatants of LPS-treated and of combined TNFalpha/IL-1beta/LPS-treated adipocytes. SRIF protein was visualized by immunohistochemistry in explanted minced adipose tissue after overnight incubation in culture medium supplemented with combined IL-1beta and LPS. In septic patients, expression of SRIF-mRNA and SRIF protein was found in visceral, but not in sc, adipose tissue. Adipocyte mRNA abundance of SSTR 1-5 was differentially regulated by inflammatory treatments.Thus, human visceral adipose tissue secretes SRIF during inflammation and sepsis and expresses several SSTRs. It is tempting to speculate that visceral adipose tissue-derived SRIF plays a modulatory role in the immunological and metabolic response to inflammation.
Seboek D et al, J Clin Endocrinol Metab. 2004 Oct;89(10):4833-9.
|
|
The peptides encoded by the VGF gene are gaining biomedical interest and are increasingly being scrutinized as biomarkers for human disease. An endocrine/neuromodulatory role for VGF peptides has been suggested but never demonstrated. Furthermore, no study has demonstrated so far the existence of a receptor-mediated mechanism for any VGF peptide. In the present study, we provide a comprehensive in vitro, ex vivo and in vivo identification of a novel pro-lipolytic pathway mediated by the TLQP-21 peptide. We show for the first time that VGF-immunoreactivity is present within sympathetic fibres in the WAT (white adipose tissue) but not in the adipocytes. Furthermore, we identified a saturable receptor-binding activity for the TLQP-21 peptide. The maximum binding capacity for TLQP-21 was higher in the WAT as compared with other tissues, and selectively up-regulated in the adipose tissue of obese mice. TLQP-21 increases lipolysis in murine adipocytes via a mechanism encompassing the activation of noradrenaline/β-adrenergic receptors pathways and dose-dependently decreases adipocytes diameters in two models of obesity. In conclusion, we demonstrated a novel and previously uncharacterized peripheral lipolytic pathway encompassing the VGF peptide TLQP-21. Targeting the sympathetic nerve-adipocytes interaction might prove to be a novel approach for the treatment of obesity-associated metabolic complications.
Possenti R, Muccioli G, Petrocchi P et al, Biochem J. 2012 Jan 1;441(1):511-22. doi: 10.1042/BJ20111165.
|
|
Adipogenesis is regulated by a wide variety of compounds. An adipogenic cocktail containing insulin (INS), dexamethasone (DEX) and 3-isobutyl-1-methyl xanthine (IBMX) is routinely used to induce adipogenesis in 3T3-L1 preadipocytes, but the biochemical actions in adipogenesis of IBMX, a non-specific phosphodiesterase inhibitor, are not completely understood. In this study we show that C-type natriuretic peptide (CNP) is an endogenous adipogenesis regulator which can largely replace the function of IBMX. In 3T3-L1 preadipocytes, CNP potently elevated cGMP production through guanylyl cyclase-B (GC-B). Lipid droplets were evident in these cells upon stimulation with CNP for 12 days in the presence of INS and DEX, and their adiposity, evaluated by Oil Red O, was significantly higher than in cells stimulated with INS and DEX only. Membrane-permeable cGMP analogue also enhanced adiposity when cells were cultured together with INS and DEX, and KT5823, a non-specific cGMP-dependent kinase (cGK) inhibitor, suppressed the stimulatory effect of IBMX on adipogenesis, revealing that IBMX-stimulated adipogenesis is mediated through cGK. The enhancement of adiposity elicited by CNP was accompanied by increased mRNA levels of adipocyte-specific genes including those encoding peroxisome proliferator-activated receptor gamma and glucose transporter 4. Interestingly, the mRNA level of CNP itself was markedly enhanced in 3T3-L1 cells upon stimulation with INS, DEX and IBMX, reaching a maximum at 8h incubation with the cocktail. These observations suggest that the CNP/GC-B system participates in regulation of adipogenesis, particularly at an early stage in the process.
Katafuchi T, Garbers DL, Albanesi JP. Peptides. 2010 Oct;31(10):1906-11. doi: 10.1016/j.peptides.2010.06.025. Epub 2010 Jul 24.
|
|
There is a high incidence of metabolic syndrome among patients with primary aldosteronism (PA), which has been recently associated with an unfavorable cardiometabolic profile. However, the underlying mechanisms have not been clarified in detail. Characterizing aldosterone target genes in adipocytes will help elucidate the deleterious effects associated with aldosterone excess. Apelin, a novel adipokine, exerts beneficial effects on obesity-associated disorders and cardiovascular homoeostasis. The objective of the study is to investigate the effect of high aldosterone levels on apelin expression and secretion and the underlying mechanisms involved in adipocytes. In vivo, a single dose aldosterone injection acutely decreased apelin serum levels and its adipose tissues production, which demonstrated a clear inverse relationship between the level of plasma aldosterone and plasma apelin. Experiments using 3T3-L1 adipocytes showed that aldosterone decreased apelin expression and secretion in a time- and dose-dependent manner. This effect was reversed by glucocorticoid receptor (GR) antagonists or GR knockdown; meanwhile, putative HREs in the apelin promoter were identified. Subsequently, we verified that both glucocorticoids and mineralocorticoids regulated apelin expression through GR activation although no synergistic effect was observed. Additionally, detailed potential mechanisms involved a p38 MAPK signaling pathway. In conclusion, our findings strengthen a direct interaction between aldosterone and apelin in adipocytes, which has important implications for hyperaldosteronism or PA associated cardiometabolic syndrome and hoists apelin on the list of potent therapeutic target for PA.
Jiang H, Ye X, Yang Z et al, J Mol Endocrinol. 2013 Apr 2. [Epub ahead of print]
|
|
OBJECTIVES:
Pigment epithelium-derived factor (PEDF) is a noninhibitory member of the serine protease inhibitor gene family with neuroprotective, neuroproliferative, and anti-angiogenic functions. Its role in pancreatic fibrosis and neuropathy is unknown.
METHODS:
The expression and localization of PEDF were assessed by quantitative real-time (RT)-PCR, immunohistochemistry, and quantitative image analysis and correlated with neural and microvessel densities (MVDs) in the normal pancreas (n=20) and pancreatic cancer (n=55). Primary human pancreatic stellate cells (PSCs), mouse neuroblastoma, and human Schwann cells were used for functional experiments. The effect of hypoxia on PEDF production in cancer cell lines and immortalized pancreatic ductal epithelial cells was assessed by quantitative RT-PCR and enzyme-linked immunosorbent assay. The effect of recombinant PEDF on PSCs was assessed by immunoblot analysis.
RESULTS:
PEDF expression was homogeneous in epithelial cells of the normal pancreas where some acinar cells consistently displayed stronger staining. A higher expression was found in tubular complexes, PanIN lesions, and inflammatory cells in pancreatic cancer. Cancer cells expressed various levels of PEDF. In cancer cell lines and in human immortalized pancreatic ductal epithelial cells, hypoxia increased PEDF mRNA up to 132-fold. Higher expression of PEDF in cancer cells was significantly correlated with better patient survival (median survival 21.5 months vs. 17.5 months, P=0.043), increased neuropathy (P=0.0251), increased PSC activity, and extracellular matrix protein production.
CONCLUSIONS:
PEDF increases PSC activity, thereby contributing to the desmoplasia of pancreatic cancer. PSC overactivation likely leads to periacinar fibrosis and degeneration of fine acinar innervation. Increased focal PEDF expression in cancer cells correlates with neuropathic changes and better patient survival.
Samkharadze T, Erkan M, Reiser-Erkan C et al, Am J Gastroenterol. 2011 May;106(5):968-80. doi: 10.1038/ajg.2010.479. Epub 2011 Jan 11.
|
|
|
|
|
|
|
