Regulates Adiponectin Secretion Research Articles

Dietary apigenin ameliorates obesity-related hypertension through TRPV4-dependent vasorelaxation and TRPV4-independent adiponectin secretion

BackgroundObesity-related hypertension is a major cardiovascular risk factor. Apigenin, a natural flavonoid in celery, induces vascular dilation via endothelial transient receptor potential channel vanilla 4 (TRPV4) channels. This study aimed to explore apigenin's potential to alleviate obesity-related hypertension in mice and its underlying mechanisms. MethodsThe C57BL/6 and TRPV4 knockout mice were fed a high-fat diet and subjected to dietary intervention with apigenin. Body weight and tail blood pressure of the mice were measured during the feeding. Vascular reactivity was assessed through a DMT wire myograph systems in vitro. The distribution and expression of adiponectin and pro-inflammatory markers in brown fat were detected. Injecting adeno-associated eight (AAV8) viruses into brown adipose tissue (BAT) to determine whether adiponectin is indispensable for the therapeutic effect of apigenin. Palmitic acid (PA) was used in mouse brown adipocytes to examine the detailed mechanisms regulating adiponectin secretion. ResultsApigenin improved vasodilation and reduced blood pressure in obese mice, effects partly blocked in TRPV4 knockout. It also reduced weight gain independently of TRPV4. Apigenin increased adiponectin secretion from BAT; knockdown of adiponectin weakened its benefits. Apigenin downregulated Cluster of differentiation 38 (CD38), restoring Nicotinamide adenine dinucleotide+ (NAD+) levels and activating the NAD+/Sirtuin 1 (SIRT1) pathway, enhancing adiponectin expression. ConclusionsOur study indicates that dietary apigenin is suitable as a nonpharmaceutical intervention for obesity-related hypertension. In mechanism, in addition to improving vascular relaxation through the activation of endothelial TRPV4 channels, apigenin also directly alleviated adipose inflammation and increased adiponectin levels by inhibiting CD38.

Growth hormone improves insulin resistance in visceral adipose tissue after duodenal-jejunal bypass by regulating adiponectin secretion

BACKGROUND The mechanism of improvement of type 2 diabetes after duodenal-jejunal bypass (DJB) surgery is not clear. AIM To study the morphological and functional changes in adipose tissue after DJB and explore the potential mechanisms contributing to postoperative insulin sensitivity improvement of adipose tissue in a diabetic male rat model. METHODS DJB and sham surgery was performed in a-high-fat-diet/streptozotocin-induced diabetic rat model. All adipose tissue was weighed and observed under microscope. Use inguinal fat to represent subcutaneous adipose tissue (SAT) and mesangial fat to represent visceral adipose tissue. RNA-sequencing was utilized to evaluate gene expression alterations adipocytes. The hematoxylin and eosin staining, reverse transcription-quantitative polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay were used to study the changes. Insulin resistance was evaluated by immunofluorescence. RESULTS After DJB, whole body blood glucose metabolism and insulin sensitivity in adipose tissue improved. Fat cell volume in both visceral adipose tissue (VAT) and SAT increased. Compared to SAT, VAT showed more significantly functional alterations after DJB and KEGG analysis indicated growth hormone (GH) pathway and downstream adiponectin secretion were involved in metabolic regulation. The circulating GH and adiponectin levels and GH receptor and adiponectin levels in VAT increased. Cytological experiment showed that GH stimulated adiponectin secretion and improve insulin sensitivity. CONCLUSION GH improves insulin resistance in VAT in male diabetic rats after receiving DJB, possibly by increasing adiponectin secretion.

Insulin Increases Adipose Adiponectin in Pregnancy by Inhibiting Ubiquitination and Degradation: Impact of Obesity.

Circulating adiponectin levels are decreased in pregnant women with obesity or gestational diabetes, and this is believed to contribute to the insulin resistance and increased risk of fetal overgrowth associated with these conditions. However, the molecular mechanisms regulating adiponectin secretion from maternal adipose tissues in pregnancy are poorly understood. We tested the hypothesis that obesity in pregnancy is associated with adipose tissue insulin resistance and increased adiponectin ubiquitination and degradation, caused by inflammation and endoplasmic reticulum (ER) stress. Visceral adipose tissues were collected from lean and obese pregnant humans and mice. Total and ubiquitinated adiponectin, and markers of inflammation, ER stress, and insulin resistance were examined in adipose tissues. The role of insulin, inflammation, and ER stress in mediating adiponectin ubiquitination and degradation was examined using 3T3L-1 adipocytes. Obesity in pregnancy is associated with adipose tissue inflammation, ER stress, insulin resistance, increased adiponectin ubiquitination, and decreased total abundance of adiponectin. Adiponectin ubiquitination was increased in visceral fat of obese pregnant women as compared to lean pregnant women. We further observed that insulin prevents, whereas ER stress and inflammation promote, adiponectin ubiquitination and degradation in differentiated 3T3-L1 adipocytes. We have identified adiponectin ubiquitination as a key mechanism by which obesity diminishes adiponectin secretion in pregnancy. This information will help us better understand the mechanisms controlling maternal insulin resistance and fetal growth in pregnancy and may provide a foundation for the development of strategies aimed at improving adiponectin production in pregnant women with obesity or gestational diabetes.

1897-P: BECN1, a Key Autophagy Protein, Regulates Adiponectin Secretion in Adipocytes by Interacting with the Exocyst Components

Autophagy is a lysosomal degradation pathway that plays pivotal roles in maintaining cellular homeostasis. Beclin1/BECN1 is a key autophagy protein that regulates the stability and kinase activity of the class III phosphatidylinositol 3-kinase complex. Dysregulation of autophagy results in the pathogenesis of a variety of diseases, including type 2 diabetes. However, the molecular mechanism of the autophagy machinery in metabolic regulation is poorly understood. To elucidate how autophagy and BECN1 are involved in energy homeostasis and insulin sensitivity, we generated a unique knock-in mouse model showing hyperactive autophagy. This mouse model carries a single amino acid substitution (F121A) in the BECN1 protein (BECN1F121A), which disrupts an inhibitory binding between BECN1 and BCL2, leading to constitutive activation of autophagy. Using this moue model, we discovered that in addition to a role in autophagic regulation, BECN1 also executes a non-degradative function. We found that in response to high-fat diet feeding, BECN1F121A mice show improved systemic insulin sensitivity, elevated adiponectin levels in the circulation, and enhanced adiponectin signaling in metabolic tissues, compared to wild type (WT) mice, despite that body weight and white adipose tissue weight are similar between the two genotypes. Using adipocyte-differentiated stromal vascular fraction cells, we further found that compared to WT BECN1, the BECN1F121A mutant interacts more strongly with components of the exocyst, a complex required for secretory vesicle docking at the plasma membrane. Finally, we demonstrated that the BECN1-exocyst interaction is mechanistically mediated through the coiled-coil domain of BECN1. Altogether, our findings suggest that BECN1 regulates adiponectin secretion through interacting with the exocyst in white adipose tissues, and highlight that autophagy proteins may play important non-degradative roles in energy metabolism. Disclosure K. Kuramoto: None. C. He: None.

168-OR: Autophagy Improves Insulin Sensitivity by Regulating Adiponectin Secretion

Autophagy is an essential lysosomal degradation pathway induced by stress. Although emerging evidence suggests that autophagy abnormality is implicated in metabolic dysfunction, the mechanism by which autophagy regulates insulin sensitivity is obscure. We recently identified a point mutation in the autophagy gene Becn1 (Becn1F121A) that leads to constitutive activation of autophagy, and generated Becn1F121A knockin mice of hyperactive autophagy. In response to high-fat diet feeding, the autophagy-hyperactive Becn1F121A mice show improved insulin sensitivity, and enhanced insulin-Akt signaling in tissues. We found that their metabolic tissues have higher activation of AMPK, which plays a central beneficial role in energy homeostasis. In addition, when added to cell culture media, serum from Becn1F121A mice can also enhance AMPK activation in the cells, suggesting a role of circulating factors in Becn1F121A-induced metabolic benefits. To further identify the autophagy-controlled circulating factor, we did a Luminex array on metabolic hormones in serum of WT and Becn1F121A mice, and detected a higher circulating level of adiponectin in Becn1F121A mice. Moreover, primary adipocytes isolated from Becn1F121A mice also secrete more adiponectin to medium, suggesting that Becn1F121A-induced adiponectin secretion is cell-autonomous. Adiponectin is an adipocyte-derived hormone that has antidiabetic effects via activating AMPK, and its blood level positively correlates with insulin sensitivity. Using biochemical approaches, we identified an interaction between Becn1 and exocyst components, and demonstrated that the Becn1F121A mutant shows higher affinity with the exocyst machinery. These data suggest that autophagy activation may improve insulin sensitivity by promoting exocyst function and adiponectin exocytosis. Our ongoing research will demonstrate for the first time how autophagy promotes adiponectin secretion, as a new mechanism by which autophagy improves metabolism. Disclosure K. Kuramoto: None. C. He: None.

Variation in x-box binding protein 1 (XBP1) expression and its dependent endoplasmic reticulum chaperones does not regulate adiponectin secretion in dairy cows

Adiponectin is an insulin-sensitizing hormone produced predominantly by adipose tissue; it circulates as oligomers of 3, 6, 18, or more units. Plasma adiponectin might be involved in the development of insulin resistance in transition dairy cows because it falls to a nadir around parturition. The possibility that this regulation occurs through a post-transcriptional mechanism was suggested in a previous study that showed unchanged adiponectin mRNA abundance combined with reduced expression of endoplasmic reticulum (ER) chaperones implicated in assembly of adiponectin oligomers. Expression of ER chaperones is controlled by x-box binding protein 1 (XBP1) and activating transcription factor 6 (ATF6), suggesting a model whereby transcriptional regulation of ER chaperones during the transition period contributes to the regulation of adiponectin production. In support of this model, XBP1 expression in adipose tissue, measured either as the active spliced XBP1 mRNA or as the total of all XBP1 mRNA isoforms, was 45% lower on d 8 of lactation than 4 wk before parturition; ATF6 mRNA abundance remained unchanged over the same period. To assess the functional importance of XBP1, preadipocytes isolated from pregnant cows were differentiated into adipocytes that secrete adiponectin. Infection of differentiating cells with an adenovirus expressing the active spliced version of bovine XBP1 did not alter adiponectin mRNA but increased the expression of ER chaperones 1.5- to 5-fold. Despite the latter, XBP1 overexpression did not affect the total amount of adiponectin secreted in medium. In additional experiments, adiponectin production was dependent on exogenous lipid in the medium and was reduced during incubation with tumor necrosis factor-α (TNFα). Accordingly, we asked whether the repressive effects of these factors on adiponectin production were related to a reduction in the expression of adiponectin or determinants of ER function (XBP1, ATF6, and ER chaperones). Exogenous lipid had no effect on the expression of any of these genes, whereas TNFα repressed adiponectin mRNA abundance by 61% but had little effect on determinants of ER function. Overall, this work shows that XBP1 is a positive regulator of ER chaperone expression in adipose tissue but provides no support for XBP1 and its dependent ER chaperones in the regulation of adiponectin production in bovine adipocytes. Mechanisms accounting for reduced plasma adiponectin in transition cows remain poorly understood.

Food habits of medical students: A study among the students of a health university in Eastern India

Type 2 diabetes mellitus (T2DM) is the most common type of diabetes, accounting for 90% of diabetic cases. It is characterized by chronic hyperglycemia which is caused by a combination of deficiency in insulin action and secretion. Adipose tissue regulates insulin sensitivity via the circulating adipocytokines, leptin, resistin and adiponectin. Hypoadiponectinemia contributes to the development of obesity and related disorders such as diabetes, hyperlipidemia and cardiovascular diseases. The present study aimed to evaluate the beneficial effect of flavonoid 2-hydroxychalcone in T2DM through its effect on peroxisome proliferator activated receptor gamma (PPAR-γ) and adiponectin. T2DM was induced in male Wistar rats using high fat diet and low dose of streptozotocin (STZ, 35 mg/kg, i.p.). The flavonoid 2-hydroxychalcone was administered by oral tubes. Levels of PPAR-γ in sub abdominal adipose tissue, serum adiponectin, serum tumor necrosis factor-α (TNF-α) and serum insulin levels were detected by ELISA. Moreover, malondialdehyde (MDA) and reduced glutathione (GSH) in sub abdominal adipose tissue, fasting serum glucose, serum triglycerides and serum total cholesterol levels were measured by colorimetric methods. Results showed that 2-hydroxychalcone attenuated changes induced by T2DM in rats. 2-Hydroxychalcone treatment increased PPAR-γ levels in adipose tissue, reduced oxidative stress, restored adiponectin levels and decreased high glucose levels in T2DM rats. In conclusion, 2-hydroxychalcone reduced hyperglycemia in T2DM by regulating adiponectin secretion. This effect involves PPAR-γ signaling pathway.

Effect of 2-hydroxychalcone on adiponectin level in type 2 diabetes induced experimentally in rats

Type 2 diabetes mellitus (T2DM) is the most common type of diabetes, accounting for 90% of diabetic cases. It is characterized by chronic hyperglycemia which is caused by a combination of deficiency in insulin action and secretion. Adipose tissue regulates insulin sensitivity via the circulating adipocytokines, leptin, resistin and adiponectin. Hypoadiponectinemia contributes to the development of obesity and related disorders such as diabetes, hyperlipidemia and cardiovascular diseases. The present study aimed to evaluate the beneficial effect of flavonoid 2-hydroxychalcone in T2DM through its effect on peroxisome proliferator activated receptor gamma (PPAR-γ) and adiponectin. T2DM was induced in male Wistar rats using high fat diet and low dose of streptozotocin (STZ, 35mg/kg, i.p.). The flavonoid 2-hydroxychalcone was administered by oral tubes. Levels of PPAR-γ in sub abdominal adipose tissue, serum adiponectin, serum tumor necrosis factor-α (TNF-α) and serum insulin levels were detected by ELISA. Moreover, malondialdehyde (MDA) and reduced glutathione (GSH) in sub abdominal adipose tissue, fasting serum glucose, serum triglycerides and serum total cholesterol levels were measured by colorimetric methods. Results showed that 2-hydroxychalcone attenuated changes induced by T2DM in rats. 2-Hydroxychalcone treatment increased PPAR-γ levels in adipose tissue, reduced oxidative stress, restored adiponectin levels and decreased high glucose levels in T2DM rats. In conclusion, 2-hydroxychalcone reduced hyperglycemia in T2DM by regulating adiponectin secretion. This effect involves PPAR-γ signaling pathway.

Novel intracellular mediator of adiponectin secretion from adipocytes.

Mature white fat cells (adipocytes) are unusual terminally differentiated cells because of their large spherical shape, the fact that their presence is not fixed at a particular location in the body, the fact that they can proliferate in various ways and the weird intracellular structures that permit a unilocular lipid droplet to occupy a large part of the intracellular space, allowing only a small crescent-shaped cytoplasmic space in which all cellular events occur (Sugihara et al. 1987). Since the verification of the hypothesis that insulin stimulates the translocation of glucose transporter (GLUT4) vesicles from intracellular storage to the plasma membrane in isolated rat adipocytes, thus increasing the cellular uptake of glucose (Cushman & Wardzala, 1980; Suzuki & Kono, 1980), the mechanism(s) of vesicular trafficking in fat cells have been the subject of many research studies. Over 10 years later, the discoveries of a number of biologically active cytokines derived from adipocytes, generally named adipokines, have changed the viewpoint, with adipocytes now being considered an endocrine organ rather than a simple energy storage organ. Of the various adipokines, adiponectin has attracted the most studies because of its protective roles against obesity-related diseases, including type-2 diabetes and cardiovascular diseases, and the reports that the reduction in the plasma level of adiponectin in obese subjects precedes the reduction in insulin sensitivity and onset of diabetes (Trujillo & Scherer, 2005; Smith & Minson, 2012; Yamauchi & Kadowaki, 2013). Most of the studies concerning adiponectin secretion have therefore been focused on the long-term chronic regulation, whereas the short-term (≤30 min) regulation of adipocyte exocytosis by intracellular mediators is not well understood. In this issue of The Journal of Physiology, Komai et al. (2014) describe a novel mechanism underlying the short-term regulation of adiponectin secretion, in 3T3-L1 adipocytes derived from mice, using a combination of membrane capacitance patch-clamp recordings and measurements of secreted adiponectin. The mechanism regulating adiponectin secretion is fundamentally different from that occurring in other endocrine cells. The authors demonstrate that the final step of adiponectin secretion in mature adipocytes, the release of adipokines from vesicles fused with the plasma membrane, is stimulated by cAMP and an exchange protein activated by cAMP (Epac), without depending on Ca2+ or protein kinase A (PKA). Biochemical measurements showed that adiponectin is the dominant adipokine secreted in a cAMP/Epac-dependent manner, whereas the amounts of other secreted adipokines, such as leptin, resistin and apelin, are very low. Interestingly, Ca2+ was shown to have no apparent effect on the final step of adipokine release, although most neurotransmitter release is considered to be Ca2+ dependent. However, the role of Ca2+ is important in the early steps of exocytosis when the secretion vesicles are recruited and refilled with adiponectin to form ready-to-release vesicles. The regulation of the entire process of adiponectin secretion in adipocytes is thus proposed to be a sequential regulation by Ca2+ and cAMP, and ATP may provide energy and substrates for the phosphorylation of proteins that play a role in exocytosis. The findings thus indicate that all three intracellular mediators, Ca2+, ATP and cAMP, are required to accomplish the short-term secretion of adiponectin, through Ca2+ and ATP, and cAMP regulates different steps of the exocytosis. In human subcutaneous adipocytes, the adiponectin secretion was also shown to be cAMP-dependent, similar to that observed in 3T3-L1 adipocytes. There is increasing evidence that obesity is associated with not only metabolic syndrome and atherosclerosis, but also non-alcoholic steatohepatitis (NASH), cancer and Alzheimer's disease, and adiponectin plays a pleiotropic role in protecting against such diseases (Smith & Minson, 2012; Yamauchi & Kadowaki, 2013). Adiponectin is thus expected to be a valuable target molecule for therapeutics supporting a healthy, long life in humans. The key findings that each step of the short-term regulation of adiponectin secretion and the packaging of vesicles is individually regulated by cAMP, Ca2+ and ATP would provide a pin-point therapeutic approach for obesity-related diseases. In white adipocytes, the binding of insulin to the receptor located on the plasma membrane is a trigger for a number of dynamic cellular events, including translocation of GLUT4 vesicles, the secretion of adiponectin and other adipokines, which are controlled in different ways. It is amazing that these complex mechanisms are well organized in the small crescent-shaped cytoplasmic space of the fat cells.

SIRT1 in Type 2 Diabetes: Mechanisms and Therapeutic Potential

The prevalence of type 2 diabetes mellitus (T2DM) has been increasing worldwide. Therefore, a novel therapeutic strategy by which to prevent T2DM is urgently required. Calorie restriction (CR) can retard the aging processes, and delay the onset of numerous age-related diseases including diabetes. Metabolic CR mimetics may be therefore included as novel therapeutic targets for T2DM. Sirtuin 1 (SIRT1), a NAD+-dependent histone deacetylase that is induced by CR, is closely associated with lifespan elongation under CR. SIRT1 regulates glucose/lipid metabolism through its deacetylase activity on many substrates. SIRT1 in pancreatic β-cells positively regulates insulin secretion and protects cells from oxidative stress and inflammation, and has positive roles in the metabolic pathway via the modulation in insulin signaling. SIRT1 also regulates adiponectin secretion, inflammation, glucose production, oxidative stress, mitochondrial function, and circadian rhythms. Several SIRT1 activators, including resveratrol have been demonstrated to have beneficial effects on glucose homeostasis and insulin sensitivity in animal models of insulin resistance. Therefore, SIRT1 may be a novel therapeutic target for the prevention of T2DM, implicating with CR. In this review, we summarize current understanding of the biological functions of SIRT1 and discuss its potential as a promising therapeutic target for T2DM.

Regulation of adiponectin secretion and expression by insulin and β‐agonists in rat

AbstractThe adipocytokines, including adiponectin, are important factors in the regulation of insulin sensitivity and carbohydrate and lipid metabolism. It is proved that concentrations of adiponectin are decreased in obesity, an insulin resistant state. The current study is to address potential mechanisms regulating adiponectin secretion and expression in vivo. To observe the regulation of adiponectin by fasting‐refeeding and β‐agonists, male Wistar rats were fasted for 18 h and allowed to refeed with/without a β3‐adrenergic receptor agonist infused into refeeding rats. We also investigated the effects of insulin clamp on adiponectin secretion and expression, including euglycemic–hyperinsulinemic clamp and hyperglycemic–hyperinsulinemic clamp. Plasma adiponectin levels were determined by radioimmunoassay. Using real‐time PCR assays, we analyzed the expression of adiponectin genes in rat primary adipocytes. Refeeding of 18‐h fasted rats increased plasma adiponectin concentration (∼2‐fold) and adipose tissue adiponectin expression (∼3‐fold), and these effects were mimicked by hyperinsulinemia in the absence of refeeding and completely blocked by administration of β‐agonists during refeeding. We conclude that (i) adiponectin secretion and expression are acutely regulated in vivo by nutritional status; (ii) in vivo, insulin and β‐agonists act directly at the adipocyte to regulate adiponectin secretion and expression.

Negative regulation of adiponectin secretion by receptor interacting protein 140 (RIP140)

RIP140 (receptor-interacting protein 140) is highly expressed in mature adipocytes and functions as a co-repressor for gene expression involved in lipid and glucose metabolism. In adipocytes, activated PKCε (Protein kinase C epsilon) phosphorylates nuclear RIP140 which is then subsequently arginine methylated and exported to the cytoplasm. In the cytoplasm, RI140 can elicit additional activities. Here we report a new functional role for cytoplasmic RIP140 in adipocyte in regulating adiponectin secretion. Targeting cytoplasmic RIP140 by knocking down RIP140 itself or its nuclear export trigger, PKCε, promotes the secretion of adiponectin without affecting the production or oligomerization of adiponectin. Consequentially, conditioned media from either RIP140- or PKCε-silenced adipocytes, which contain higher levels of adiponectin, enhance glucose uptake in C2C12 cells and reduce gluconeogenesis in HepG2 cells. Further, these effects can be inhibited by an adiponectin-neutralizing antibody. The effect of cytoplasmic RIP140 in regulating adiponectin secretion is via interacting with AS160, a known RIP140-interacting protein. This study reveals a new functional role for cytoplasmic RIP140 in modulating adiponectin vesicle secretion, and suggests that targeting cytoplasmic RIP140 may be a potentially effective therapeutic strategy to improve adiponectin secretion and possibly to manage metabolic disorders.

SIRT1 and insulin resistance

Sirtuin 1 (SIRT1), the mammalian homolog of SIR2, was originally identified as a NAD-dependent histone deacetylase, the activity of which is closely associated with lifespan under calorie restriction. Growing evidence suggests that SIRT1 regulates glucose or lipid metabolism through its deacetylase activity for over two dozen known substrates, and has a positive role in the metabolic pathway through its direct or indirect involvement in insulin signaling. SIRT1 stimulates a glucose-dependent insulin secretion from pancreatic beta cells, and directly stimulates insulin signaling pathways in insulin-sensitive organs. Furthermore, SIRT1 regulates adiponectin secretion, inflammatory responses, gluconeogenesis, and levels of reactive oxygen species, which together contribute to the development of insulin resistance. Moreover, overexpression of SIRT1 and several SIRT1 activators has beneficial effects on glucose homeostasis and insulin sensitivity in obese mice models. These findings suggest that SIRT1 might be a new therapeutic target for the prevention of disease related to insulin resistance, such as metabolic syndrome and diabetes mellitus, although direct evidence from clinical studies in humans is needed to prove this possibility. In this Review, we discuss the potential role and therapeutic promise of SIRT1 in insulin resistance on the basis of the latest experimental studies.

The effects of hydroxycinnamic acid derivatives on adiponectin secretion

Adiponectin is positively correlated with insulin sensitivity. Hydroxycinnamic acid derivatives (HADs), observed ubiquitously in plants, have some physiological functions. In this study, we investigated the effect of HADs on serum adiponectin concentrations in mice and on adiponectin secretion of 3T3-L1 adipocytes. In mice, serum adiponectin concentrations were increased by gamma-oryzanol administration. CAPE, curcumin, and trans-ferulic acid markedly enhanced the adiponectin secretion of 3T3-L1 adipocytes, but not gamma-oryzanol. To clarify the effects of gamma-oryzanol in mice or the effects of HADs on the underlying mechanisms of adiponectin secretion, we further investigated the effect of HADs on adiponectin secretion in the NF-kappaB activation state. Although the adiponectin secretion was reduced in the presence of lipopolysaccharide plus TNF-alpha and IFN-gamma, only gamma-oryzanol supported the activity of adiponectin secretion under NF-kappaB activated condition. The results indicate that these HADs might regulate adiponectin secretion by the inhibition of NF-kappaB activation. HADs might be effective for ameliorating type 2 diabetes.

Fish Oil Regulates Adiponectin Secretion by a Peroxisome Proliferator–Activated Receptor-γ–Dependent Mechanism in Mice

Adiponectin has insulin-sensitizing, antiatherogenic, and anti-inflammatory properties, but little is known about factors that regulate its secretion. To examine the effect of fish oil on adiponectin secretion, mice were fed either a control diet or isocaloric diets containing 27% safflower oil or 27, 13.5, and 8% menhaden fish oil. Within 15 days, fish oil feeding raised plasma adiponectin concentrations two- to threefold in a dose-dependent manner, and the concentrations remained approximately twofold higher for 7 days when the fish oil diet was replaced by the safflower oil diet. Within 24 h, fish oil markedly induced transcription of the adiponectin gene in epididymal adipose tissue but not in subcutaneous fat. The increase of plasma adiponectin by fish oil was completely blocked by administration of the peroxisome proliferator-activated receptor (PPAR)gamma inhibitor bisphenol-A-diglycidyl ether. In contrast, there was no effect of fish oil feeding on adiponectin secretion in PPARalpha-null mice. These data suggest that fish oil is a naturally occurring potent regulator of adiponectin secretion in vivo and that it does so through a PPARgamma-dependent and PPARalpha-independent manner in epididymal fat.

Prolactin and growth hormone regulate adiponectin secretion and receptor expression in adipose tissue

Adiponectin is a hormone secreted from adipose tissue, and serum levels are decreased with obesity and insulin resistance. Because prolactin (PRL) and growth hormone (GH) can affect insulin sensitivity, we investigated the effects of these hormones on the regulation of adiponectin in human adipose tissue in vitro and in rodents in vivo. Adiponectin secretion was significantly suppressed by PRL and GH in in vitro cultured human adipose tissue. Furthermore, PRL increased adiponectin receptor 1 (AdipoR1) mRNA expression and GH decreased AdipoR2 expression in the cultured human adipose tissue. In transgenic mice expressing GH, and female mice expressing PRL, serum levels of adiponectin were decreased. In contrast, GH receptor deficient mice had elevated adiponectin levels, while PRL receptor deficient mice were unaffected. In conclusion, we demonstrate gene expression of AdipoR1 and AdipoR2 in human adipose tissue for the first time, and show that these are differentially regulated by PRL and GH. Both PRL and GH reduced adiponectin secretion in human adipose tissue in vitro and in mice in vivo. Decreased serum adiponectin levels have been associated with insulin resistance, and our data in human tissue and in transgenic mice suggest a role for adiponectin in PRL and GH induced insulin resistance.