Dysregulation Of Adipokines Research Articles

Abstract 2560: Post-translational modification of focal adhesion kinase (FAK) protein increases in breast cancer cells upon exposure to conditioned medium derived from in vitro and in vivo adipocytes

Abstract Under obese conditions, dysregulation of the normal secretion of adipokines from fat cells has been shown to drive cancer progression. However, the role adipokine dysregulation plays in driving metastasis is still unclear. Recent studies have reported the activation of metastasis-associated cell signaling pathways. One such pathway involves Focal Adhesion Kinase (FAK), a non-receptor cytoplasmic protein that acts as a signal transducer between receptor activation by adipokines and downstream effector proteins that control the biological phenomenon of metastasis. Nevertheless, the association between obesity-induced changes in adipocyte secretory factors and the subsequent increase in the transactivation of FAK through phosphorylation is unknown. To elucidate the potential relationship of adipocyte-secreted factors towards activating FAK, breast cancer cells with low (MCF7) and high (MDA-MB-231) metastatic potential were exposed to in vitro and in vivo, murine adipocyte-derived, conditioned medium. For the in vitro adipocyte model, 3T3-L1 MBX cells differentiated to obesity, with fatty acids supplementation, were used. For the in vivo model, adipocyte-secreted factors from organ-cultured visceral fat harvested from C3H/HeJ female mice fed an either high fat (46%) or control (11%) diets, were collected in the medium. Adipocyte secretions from the in vitro and in vivo adipocyte samples were determined using a mouse adipokine proteomic profiler array and ELISA kit. Under obese conditions, both the 3T3-L1 MBX cells and C3H/HeJ visceral fat were found to have significant changes in their adipokine secretions in comparison to controls. Results showed that the breast cancer cells got increased FAK autophosphorylation when exposed to either in vitro or in vivo-derived obese adipocyte-conditioned medium in comparison to the untreated breast cancer cells. Citation Format: Noshin Mubtasim, Caleb Boren, Benjamin Barr, Lauren Gollahon. Post-translational modification of focal adhesion kinase (FAK) protein increases in breast cancer cells upon exposure to conditioned medium derived from in vitro and in vivo adipocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2560.

The associations of adipokines with hypertension in youth with cardiometabolic risk and the mediation role of insulin resistance: The BCAMS study.

The mechanisms link obesity and hypertension are not well understood. One possibility is the alterations in adipose-derived adipokines that modulate insulin resistance (IR) and cardiovascular homeostasis. We aimed to assess the associations between hypertension and four adipokine levels in Chinese youth, and to examine to what extent the associations are mediated by IR. We utilized cross-sectional data from the Beijing Children and Adolescents Metabolic Syndrome (BCAMS) Study Cohort (n = 559, mean age = 20.2 years). Plasma leptin, adiponectin, retinol binding protein 4 (RBP4) and fibroblast growth factor 21 (FGF21) levels were assayed. The relationships between adipokines and hypertension and the possible mediation effect of IR were evaluated. Youth with hypertension have lower adiponectin and higher leptin, FGF21 (all P < 0.001) and RBP4 levels (p = 0.06) compared to their counterparts. Moreover, the co-existence of these two or more adipokine abnormalities in youth leads to a 9-fold increased risk for hypertension (OR: 9.19; 95% CI, 4.01-21.08) compared with these without abnormalities. However, in the fully adjusted and BMI-adjusted analyses, only FGF21 was a significant predictor of hypertension (OR: 2.12; 95% CI, 1.34-3.36). Mediation analysis revealed that the associations between leptin, adiponectin, RBP4 and hypertension are totally mediated by IR (proportion: 63.9%, 65.4%, and 31.6%, respectively), while BMI and IR partly mediated the association between FGF21 and hypertension (proportion: 30.6%, 21.2%). Our findings suggest that dysregulation of adipokines might result in hypertension in youth. Leptin, adiponectin and RBP4 may exert their functions in hypertension through adiposity-related IR, whereas FGF21 might be used as an independent marker of hypertension in youth.

Visceral fat and attribute-based medicine in chronic kidney disease.

Visceral adipose tissue plays a central role in obesity and metabolic syndrome and is an independent risk factor for both cardiovascular and metabolic disorders. Increased visceral adipose tissue promotes adipokine dysregulation and insulin resistance, leading to several health issues, including systemic inflammation, oxidative stress, and activation of the renin-angiotensin-aldosterone system. Moreover, an increase in adipose tissue directly and indirectly affects the kidneys by increasing renal sodium reabsorption, causing glomerular hyperfiltration and hypertrophy, which leads to increased proteinuria and kidney fibrosis/dysfunction. Although the interest in the adverse effects of obesity on renal diseases has grown exponentially in recent years, the relationship between obesity and renal prognosis remains controversial. This may be attributed to the long clinical course of obesity, numerous obesity-related metabolic complications, and patients' attributes. Multiple individual attributes influencing the pathophysiology of fat accumulation make it difficult to understand obesity. In such cases, it may be effective to elucidate the pathophysiology by conducting research tailored to individual attributes from the perspective of attribute-based medicine/personalized medicine. We consider the appropriate use of clinical indicators necessary, according to attributes such as chronic kidney disease stage, level of visceral adipose tissue accumulation, age, and sex. Selecting treatments and clinical indicators based on individual attributes will allow for advancements in the clinical management of patients with obesity and chronic kidney disease. In the clinical setting of obesity-related nephropathy, it is first necessary to accumulate attribute-based studies resulting from the accurate evaluation of visceral fat accumulation to establish evidence for promoting personalized medicine.

Correlates of Insulin Resistance in Nascent Metabolic Syndrome.

Metabolic Syndrome (MetS), a major global problem, is a cluster of cardio-metabolic risk factors that predisposes to both type 2 diabetes mellitus (T2DM) and premature atherosclerotic cardiovascular disease (ASCVD). Insulin resistance is a major underpinning of MetS. We investigated the relationship between insulin resistance and biomarkers of inflammation, oxidative stress, free fatty acids (FFA) levels and adipokine dysregulation in a cohort of nascent MetS. This was a cross-sectional study comparing patients with MetS with matched controls. Participants included 47 patients with MetS and 41 controls. Persons with diabetes, ASCVD, smoking and macro-inflammation were excluded. Fasting blood was obtained for both plasma and monocyte isolation. Homeostasis model assessment insulin resistance index (HOMA-IR) was calculated from fasting glucose and insulin levels. The patients were insulin resistant as determined by a valid measure, HOMA-IR. HOMA-IR increased with increasing severity of MetS and correlated with cardio-metabolic features, hsCRP, FFA levels, and adipose tissue insulin resistance. Insulin resistance also correlated with biomarkers of oxidative stress and both circulating and cellular biomarkers of inflammation. Receiver operating Characteristic (ROC) curve analysis revealed that HOMA-IR was an excellent predictor of MetS with an area under the curve of 0.80. In our patients with nascent MetS we show that they have significant insulin resistance. Based on our findings, elevated FFA levels, oxidative stress and inflammation could contribute to the insulin resistance.

Hepatokines and Adipokines in Metabolic Syndrome

Hepatokines and adipokines are secretory proteins derived from hepatocytes and adipocytes, respectively. These proteins play a main role in the pathogenesis of metabolic syndrome (MetS), characterized by obesity, dysglycemia, insulin resistance, dyslipidemia, and hypertension. Adipose tissue and liver are important endocrine organs because they regulate metabolic homeostasis as well as inflammation because they secrete adipokines and hepatokines, respectively. These adipokines and hepatokines communicate their action through different autocrine, paracrine and endocrine pathways. Liver regulates systemic homeostasis and also glucose and lipid metabolism through hepatokines. Dysregulation of hepatokines can lead to progression toward MetS, type 2 diabetes (T2D), inflammation, hypertension, and other diseases. Obesity is now a worldwide epidemic. Increasing cases of obesity and obesity-associated metabolic syndrome has brought the focus on understanding the biology of adipocytes and the mechanisms occurring in adipose tissue of obese individuals. A lot of facts are now available on adipose tissue as well. Adipose tissue is now given the status of an endocrine organ. Recent evidence indicates that obesity contributes to systemic metabolic dysfunction. Adipose tissue plays a significant role in systemic metabolism by communicating with other central and peripheral organs via the production and secretion of a group of proteins known as adipokines. Adipokine levels regulate metabolic state of our body and are potent enough to have a direct impact upon energy homeostasis and systemic metabolism. Dysregulation of adipokines contribute to obesity, T2D, hypertension and several other pathological changes in various organs. This makes characterization of hepatokines and adipokines extremely important to understand the pathogenesis of MetS. Hepatokines such as fetuin-A and leukocyte cell-derived chemotaxin 2, and adipokines such as resistin, leptin, TNF-α, and adiponectin are some of the most studied proteins and they can modulate the manifestations of MetS. Detailed insight into the function and mechanism of these adipokines and hepatokines in the pathogenesis of MetS can show the path for devising better preventative and therapeutic strategies against this present-day pandemic.

Adipokines and incident venous thromboembolism: The Multi-Ethnic Study of Atherosclerosis

Obesity leads to adipocyte hypertrophy and adipokine dysregulation and is an independent risk factor for venous thromboembolism (VTE). However, the association between adipokines and VTE is not well established. To examine whether adipokines are associated with increased risk of incident VTE. We studied 1888 participants of the Multi-Ethnic Study of Atherosclerosis cohort who were initially free of VTE and had adipokine (adiponectin, leptin, and resistin) levels measured at either examination 2 or 3 (2002-2004 or 2004-2005, respectively). During follow-ups, VTE was ascertained through hospitalization records and death certificates by using ICD-9 and 10 codes. We used multivariable Cox proportional hazards regression to assess the association between 1 standard deviation (SD) log-transformed increments in adipokines and incident VTE. The mean± SD age was 64.7± 9.6 years, and 49.8% of participants were women. Medians (interquartile range) of adiponectin, leptin, and resistin were 17.3 (11.8-26.2) mcg/mL, 13.5 (5.6-28.2) ng/mL, and 15.0 (11.9-19.0) ng/mL, respectively. There were 78 incident cases of VTE after a median of 9.7 (5.0-12.4) years of follow-up. After adjusting for sociodemographics, smoking, and physical activity, the hazard ratios (95% CIs) per 1 SD increment of adiponectin, leptin, and resistin were 1.14 (0.90-1.44), 1.29 (1.00-1.66), and 1.38 (1.09-1.74), respectively. The association for resistin persisted after further adjustments for body mass index and computed tomography-derived total visceral adipose tissue area. Higher resistin levels were independently associated with greater risk of incident VTE. Larger prospective cohort studies are warranted to confirm this association.

Abstract 9385: Adipokines and Venous Thromboembolism: The Multi- Ethnic Study of Atherosclerosis (MESA)

Introduction: Obesity leads to adipocyte hypertrophy and adipokine dysregulation, with implications for cardiovascular disease. Prior studies have linked adipokines to many obesity-related pathologies, with higher adiponectin levels considered cardioprotective whereas higher leptin and resistin are generally considered deleterious to cardiovascular health. In this regard, obesity is an independent risk factor for incident venous thromboembolism [VTE (deep vein thrombosis or pulmonary embolus)]. However, the associations of adipokines with VTE are not well established. Methods: We studied 1,888 MESA participants who were initially free of VTE and had adipokine levels measured at either visit 2 or 3. VTE was ascertained through hospitalization records and death certificates using ICD-9 and 10 codes. We used multivariable Cox proportional hazards regression to assess the association between 1 standard deviation (SD) log-transformed increments in adipokines and incident VTE. Results: The mean ± SD age was 64.7 ± 9.6 years; 50% women, 40% White, 20% Black, 26% Hispanic, and 13% Chinese - American participants. Median (IQR) of adiponectin, leptin and resistin were 17.3 (11.8 - 26.2) mcg/mL ,13.5 (5.6 - 28.2) ng/mL, and 15.0 (11.9 - 19.0) ng/mL respectively. There were 78 incident cases of VTE after a median of 9.7 (5.0 - 12.4) years of follow-up. The adjusted hazard ratio (95%) per 1 SD increment of adiponectin, leptin and resistin were 1.10 (0.86 - 1.42), 1.30 (0.97 - 1.74) and 1.39 (1.10 - 1.75), respectively (Table 1, Model 1 ). Associations for resistin persisted after adjustment for body mass index (Model 2) and computed tomography derived total visceral and subcutaneous adipose tissue area (Model 3). Conclusions: In this multi-ethnic cohort of adults free of cardiovascular disease at baseline, higher resistin levels were independently associated with greater risk of incident VTE. Larger prospective cohort studies are warranted to confirm this association.

PMON307 Adipokines and Bone Health in Hispanic Children

Abstract Introduction Leptin and adiponectin are adipocytokines with important metabolic functions. Leptin to adiponectin ratio is a marker of adipose tissue dysfunction and is associated with insulin resistance and cardiometabolic risk. We previously reported a negative effect of adiposity on bone health. We examined the relationship of adipokines to bone mass in a large cohort of Hispanic youth. We hypothesized that adipocytokine dysregulation in childhood may contribute to adverse bone health in children with obesity. Methods We studied 501 (237 males and 264 females) children and adolescents from the Viva la Familia Study. They were all pubertal; mean age (SD) 14.1 (2.5) years; 27% were normal weight (NW), 20% overweight (OW) and 53% obese (OB). They underwent measurement of body composition, total body less head bone mineral content (BMC) and density (BMD) by DXA scan; fasting leptin and adiponectin. The leptin to adiponectin ratio was calculated. Results Leptin concentration and leptin to adiponectin ratio were higher in OW and OB compared to NW (p&amp;lt;.001) whereas adiponectin was lower in OW and OB compared to NW (p&amp;lt;.001). After adjusting for sex, age, Tanner stage and lean mass, BMC was inversely related to leptin (r = -0.15, p =.001) and leptin to adiponectin ratio (r = -0.20, p &amp;lt;.001) but positively related to adiponectin (r = 0.12, p =.007). Similar relationships were found for BMD. In a regression model with BMC as the dependent variable, together and independently of sex, age, Tanner stage, lean mass and fat mass, leptin to adiponectin ratio negatively contributed (β = -0.060, p=.002) to the variance of BMC (R2 = 0.877, p &amp;lt;.001). Similar findings were seen with BMD as the dependent variable. Conclusion Elevated leptin to adiponectin ratio, a manifestation of adipokine dysregulation, may contribute negatively to bone health (BMC and BMD) in children with overweight/obesity. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Obesity-Related High-Output Heart Failure: An Integrative Review.

High-output heart failure (HF) is a type of HF characterized by signs and symptoms of HF and a cardiac output of 8 L/min or greater or a cardiac index greater than 3.9 L/min/m 2 . High-output HF occurs secondary to an underlying condition that requires high cardiac output due to an increase in oxygen consumption or decreased systemic vascular resistance. Obesity is a major cause of high-output HF, yet there is limited research on obesity-related high-output HF. Thus, the pathophysiologic mechanisms of this syndrome are not fully understood. The objectives of this integrative review were to describe the current state of the research regarding obesity-related high-output HF and to recommend direction for future research. We conducted an integrative review focusing on the peer-reviewed literature on patients with obesity-related high-output HF using Whittemore and Knafl's methodology. MEDLINE, CINAHL, and EMBASE electronic databases were searched for all publications indexed in the databases as of March 9, 2022. A narrative synthesis of definitions and symptoms, obesity as an underlying condition, pathophysiology, and treatments of obesity-related high-output HF was completed. A total of 6 articles were included in the integrative review, with 1 nonexperimental, retrospective study and 5 literature reviews. Understanding of obesity-related high-output HF is very limited because of scant empirical evidence in the existing literature. Possible pathophysiologic mechanisms include increased pressure in the upper airways, adipokine dysregulation, increased metabolic activity, and insulin resistance. Additional research is needed on the pathophysiologic mechanisms of obesity-related high-output HF to begin investigations on therapeutic interventions to improve health outcomes.

Systematic review on serum retinol binding protein 4 (RBP4) and interrelated iron status in type 2 diabetes mellitus patients

The dysregulation of adipokines is closely associated with the pathogenesis of insulin resistance and type 2 diabetes mellitus. A recently proposed adipokine i.e., Retinol-binding protein-4 (RBP4), is found to provide a connecting link between insulin resistance and obesity. Interestingly, the interaction between vitamin A and iron status has also been observed in a few shreds of evidence. For instance, vitamin A deficiency may result in impairment of iron metabolism and may aggravate anemia. Here, the present review is designed to summarize the up-to-date knowledge on RBP4’s role in obesity, development of insulin resistance, and Type 2 Diabetes Mellitus by findings of previous studies and investigate the crucial possible outcome of the relationship between RBP4 and iron status in type 2 diabetes mellitus patients, most importantly in humans.

Vitamin C attenuates predisposition to high-fat diet-induced metabolic dysregulation in GLUT10-deficient mouse model

BackgroundThe development of type 2 diabetes mellitus (T2DM) is highly influenced by complex interactions between genetic and environmental (dietary and lifestyle) factors. While vitamin C (ascorbic acid, AA) has been suggested as a complementary nutritional treatment for T2DM, evidence for the significance and beneficial effects of AA in T2DM is thus far inconclusive. We suspect that clinical studies on the topic might need to account for combination of genetic and dietary factors that could influence AA effects on metabolism. In this study, we tested this general idea using a mouse model with genetic predisposition to diet-induced metabolic dysfunction. In particular, we utilized mice carrying a human orthologous GLUT10G128E variant (GLUT10G128E mice), which are highly sensitive to high-fat diet (HFD)-induced metabolic dysregulation. The genetic variant has high relevance to human populations, as genetic polymorphisms in glucose transporter 10 (GLUT10) are associated with a T2DM intermediate phenotype in nondiabetic population.ResultsWe investigated the impacts of AA supplementation on metabolism in wild-type (WT) mice and GLUT10G128E mice fed with a normal diet or HFD. Overall, the beneficial effects of AA on metabolism were greater in HFD-fed GLUT10G128E mice than in HFD-fed WT mice. At early postnatal stages, AA improved the development of compromised epididymal white adipose tissue (eWAT) in GLUT10G128E mice. In adult animals, AA supplementation attenuated the predisposition of GLUT10G128E mice to HFD-triggered eWAT inflammation, adipokine dysregulation, ectopic fatty acid accumulation, metabolic dysregulation, and body weight gain, as compared with WT mice.ConclusionsTaken together, our findings suggest that AA has greater beneficial effects on metabolism in HFD-fed GLUT10G128E mice than HFD-fed WT mice. As such, AA plays an important role in supporting eWAT development and attenuating HFD-induced metabolic dysregulation in GLUT10G128E mice. Our results suggest that proper WAT development is essential for metabolic regulation later in life. Furthermore, when considering the usage of AA as a complementary nutrition for prevention and treatment of T2DM, individual differences in genetics and dietary patterns should be taken into account.

Metabolically associated fatty liver disease – a disease of the 21st century: A review

Metabolically associated fatty liver disease (MAFLD) is a widespread chronic disease characterized by increased accumulation of fat in the liver, which is based on metabolic dysfunction. The incidence of MAFLD is well over 20% in most regions of the world and is on an increasing trend. Current thinking considers the etiology and pathogenesis of MAFLD under the concept of "multiple parallel blows". According to this model, the development and progression of the disease are due to the interaction of multiple genetic, environmental and adaptive factors, which include specific genetic polymorphisms (e.g., the PNPLA3 gene) and epigenetic modifications, dietary patterns (e.g. high saturated fat and fructose intake), sedentary activity, obesity, insulin resistance, dysregulation of adipokines, lipotoxicity, oxidative stress, and gut microbiota dysbiosis (small intestinal bacterial overgrowth syndrome). The basis for the diagnosis of MAFLD is the presence of proven hepatic steatosis in combination with one of the following criteria: overweight/obesity, presence of type 2 diabetes mellitus, signs of metabolic dysregulation. Nonmedicamental therapies recommended for patients with MAFLD include weight loss (if overweight or obese), reduction of saturated fatty acid and fructose intake, and inclusion of adequate amounts of omega-3 polyunsaturated fatty acids and dietary fibre (psyllium) in the diet. Pharmacotherapy of MAFLD should be aimed at correcting insulin resistance, improving liver function and reducing the risk of associated diseases.

Nil-Surin Rice Bran Hydrolysates Improve Lipid Metabolism and Hepatic Steatosis by Regulating Secretion of Adipokines and Expression of Lipid-Metabolism Genes

Overconsumption of a high caloric diet is associated with metabolic disorders and a heightened risk of diabetes mellitus (DM), hepatic steatosis, and cardiovascular complications. The use of functional food has received much attention as a strategy in the prevention and treatment of metabolic disorders. This present study investigated whether Nil-Surin rice bran hydrolysates (NRH) could prevent or ameliorate the progression of metabolic disorders in rats in which insulin resistance (IR) was induced by a high fat-high fructose diet (HFFD). After 10 weeks of the HFFD, the rats showed elevated fasting blood glucose (FBG), impaired glucose tolerance, dysregulation of adipokine secretion, distorted lipid metabolism such as dyslipidemia, and increased intrahepatic fat accumulation. The IR was significantly attenuated by a daily dose of NRH (100 or 300 mg/kg/day). Doses of NRH rectified adipokine dysregulation by increasing serum adiponectin and improving hyperleptinemia. Interestingly, NRH decreased intrahepatic fat accumulation and improved dyslipidemia as shown by decreased levels of hepatic triglyceride (TG) and serum TG, total cholesterol and low-density lipoprotein cholesterol, and increased high-density lipoprotein cholesterol. In addition, a modulation of expression of lipid metabolism genes was observed: NRH prevented upregulation of the lipogenesis genes Srebf1 and Fasn. In addition, NRH enhanced the expression of fatty-acid oxidation genes, as evidenced by an increase of Ppara and Cpt1a when compared with the HFFD control group. The activities of NRH in the modulation of lipid metabolism and rectifying the dysregulation of adipokines may result in a decreased risk of DM and hepatic steatosis. Therefore, NRH may be beneficial in ameliorating metabolic disorders in the HFFD model.

The dysregulation of adipokines in the synergy of diabetes and HIV infection

The dysregulation of adipokines in the synergy of diabetes and HIV infection

Chronic Binge Alcohol Differentially Affects Extracellular Matrix Phenotype in Omental and Subcutaneous Adipose Tissue of SIV‐infected Macaques

The incidence of at‐risk alcohol use among people living with HIV (PLWH) is two times greater than in the general population. Though antiretroviral therapy (ART) has significantly reduced HIV‐associated mortality, increased survival of PLWH on ART is associated with increased incidence of metabolic comorbidities. Adipose tissue maladaptation is central to metabolic alterations in PLWH and at‐risk alcohol use. This involves adipokine disruption, adipocyte dysfunction, inflammation, and dysregulation of the extracellular milieu. Using a relevant preclinical model of HIV‐infection, the objective of our study was to investigate the effects of chronic binge alcohol (CBA) administration on omental adipose tissue (OmAT) and subcutaneous adipose tissue (SAT) extracellular matrix (ECM) phenotype. Rhesus macaques were administered CBA or isovolumetric water (VEH) through an intragastric catheter for 30 min, 5 days a week, with blood alcohol concentrations reaching 50‐60 mM. Three months after initiation of CBA or VEH administration, macaques were inoculated with SIVMac251, and 2.5 months later animals were initiated on ART. CBA or VEH administration was continued throughout the duration of the study (14.5 mo). Animals were euthanized at 11.5 mo of SIV infection, and adipose (OmAT and SAT) samples excised. Collagen content, adipocyte diameter and adipocyte numbers were measured by Picrosirius Red Staining (PSR). A custom PCR Array was used to assess differential expression of 41 ECM‐related genes. CBA administration significantly increased collagen expression and decreased adipocyte diameter in the OmAT without altering adipocyte numbers. There was a strong negative correlation of OmAT adipocyte diameter and collagen expression. CBA administration did not result in significant differences in collagen expression, adipocyte diameter or number in SAT. CBA administration significantly upregulated expression of transforming growth factor beta‐1 (TGFB1), platelet‐derived growth factor receptor alpha (PDGFRA) and secreted protein acidic and rich in cysteine (SPARC), mediators of a pro‐fibrotic milieu in OmAT. In contrast, CBA did not significantly alter expression of ECM‐related genes in the SAT. These data suggest that the maladaptive adipose changes associated with CBA in SIV infection are depot specific. We speculate that changes in the ECM contribute to altered gene expression and impaired adipocyte metabolic capacity.

Near-roadway air pollution, immune cells and adipokines among obese young adults

BackgroundAir pollution has been associated with metabolic disease and obesity. Adipokines are potential mediators of these effects, but studies of air pollution-adipokine relationships are inconclusive. Macrophage and T cells in adipose tissue (AT) and blood modulate inflammation; however, the role of immune cells in air pollution-induced dysregulation of adipokines has not been studied. We examined the association between air pollution exposure and circulating and AT adipokine concentrations, and whether these relationships were modified by macrophage and T cell numbers in the blood and AT.MethodsFasting blood and abdominal subcutaneous AT biopsies were collected from 30 overweight/obese 18–26 year-old volunteers. Flow cytometry was used to quantify T effector (Teff, inflammatory) and regulatory (Treg, anti-inflammatory) lymphocytes and M1 [inflammatory] and M2 [anti-inflammatory]) macrophage cell number. Serum and AT leptin and adiponectin were measured using enzyme-linked immunosorbent assay (ELISA). Exposure to near-roadway air pollution (NRAP) from freeway and non-freeway vehicular sources and to regional particulate matter, nitrogen dioxide and ozone were estimated for the year prior to biopsy, based on participants’ residential addresses. Linear regression models were used to examine the association between air pollution exposures and adipokines and to evaluate effect modification by immune cell counts.ResultsAn interquartile increase in non-freeway NRAP exposure during 1 year prior to biopsy was associated with higher leptin levels in both serum [31.7% (95% CI: 10.4, 52.9%)] and AT [19.4% (2.2, 36.6%)]. Non-freeway NRAP exposure effect estimates were greater among participants with greater than median Teff/Treg ratio and M1/M2 ratio in blood, and with greater M1 counts in AT. No adipokine associations with regional air pollutants were found.DiscussionOur results suggest that NRAP may increase serum leptin levels in obese young adults, and this association may be promoted in a pro-inflammatory immune cell environment in blood and AT.

The Combination of High Levels of Adiponectin and Insulin Resistance Are Affected by Aging in Non-Obese Old Peoples.

BackgroundAdipokine dysregulation is a key feature of insulin resistance and a metabolic syndrome associated with obesity. Low adiponectin levels are associated with higher risks of cardiovascular diseases (CVD). However, high adiponectin levels have also been associated with increased all-cause and cardiovascular mortality in the elderly. This adiponectin paradox has yet to be clarified, which has hindered our understanding of the biological role of adiponectin. Adipokine dysregulation and insulin resistance are also associated with energy-deprivation conditions, such as frailty in old age. The objective of this study was to investigate the association between plasma adiponectin and insulin resistance using the homeostasis model assessment for insulin resistance (HOMA-IR) classified by age. In particular, we sought to determine the factors of the subjects associated with both high adiponectin levels and HOMA-IR (H-adiponectin/H-HOMA) and high adiponectin levels and low HOMA-IR (H-adiponectin/L-HOMA).MethodsThe eligible subjects in this cross-sectional study were 33,216 individuals who had undergone health checkups at the Physical Checkup Center of Sumitomo Hospital between April 2008 and December 2018. After excluding 26,371 individuals who were under 60 years old, 529 who had been taking medications for diabetes mellitus, and 690 with missing data, the present study included 5,673 (3,467 males, 2,206 females) subjects with no missing data. The relationship between serum adiponectin levels and HOMA-IR was assessed using logistic regression models adjusted by clinically relevant factors.ResultsIn the multivariable logistic regression analysis, age and low BMI were shown to positively correlate with the characteristics of H-adiponectin/H-HOMA. In females, systolic blood pressure was also shown to be an associated factor.ConclusionIn conclusion, this study showed that aging or a low BMI may contribute to high adiponectin levels and insulin resistance.

A new immunometabolic perspective of intervertebral disc degeneration.

Intervertebral disc (IVD) degeneration is a common finding on spine imaging that increases in prevalence with age. IVD degeneration is a frequent cause of low back pain, which is a leading cause of disability. The process of IVD degeneration consists of gradual structural change accompanied by severe alterations in metabolic homeostasis. IVD degeneration, like osteoarthritis, is a common comorbidity in patients with obesity and type 2 diabetes mellitus, two metabolic syndrome pathological conditions in which adipokines are important promoters of low-grade inflammation, extracellular matrix degradation and fibrosis. Impairment in white adipose tissue function, due to the abnormal fat accumulation in obesity, is characterized by increased production of specific pro-inflammatory proteins such as adipokines by white adipose tissue and of cytokines such as TNF by immune cells of the stromal compartment. Investigations into the immunometabolic alterations in obesity and type 2 diabetes mellitus and their interconnections with IVD degeneration provide insights into how adipokines might affect the pathogenesis of IVD degeneration and impair IVD function and repair. Toll-like receptor-mediated signalling has also been implicated as a promoter of the inflammatory response in the metabolic alterations associated with IVD and is thus thought to have a role in IVD degeneration. Pathological starvation, obesity and adipokine dysregulation can result in immunometabolic alterations, which could be targeted for the development of new therapeutics.

The Association Between Multiparity and Adipokine Levels: The Multi-Ethnic Study of Atherosclerosis.

Background: Multiparity is a risk factor for cardiovascular disease (CVD). However, the mechanisms of this relationship are unknown. Adipokines may predispose multiparous women to certain cardiometabolic complications that can increase their risk of future CVD. Materials and Methods: We studied 973 female participants of the Multi-Ethnic Study of Atherosclerosis free of CVD, who had complete data on parity and adipokines measured at Examination 2 or 3 (randomly assigned). Parity was categorized as nulliparity, 1-2, 3-4, and ≥5 live births. Multivariable linear regression was used to evaluate the association of parity with leptin, resistin, and adiponectin levels. Results: The women had mean age of 65 ± 9 years. After adjustment for age, race/ethnicity, study site, education, menopause status, smoking, physical activity, use of hormone therapy, and waist circumference, a history of grand multiparity (≥5 live births) was associated with 11% higher resistin levels (95% confidence interval [CI] 0-23) and 3-4 live births was associated with 23% higher leptin levels (95% CI 7-42), compared with nulliparity. After adjustment for computed tomography-measured visceral fat, the association of 3-4 live births with leptin remained significant. There were no significant associations of parity with adipokines after further adjustment for additional CVD risk factors. Multigravidity (but not parity) was inversely associated with adiponectin levels. Conclusions: In a multiethnic cohort of women, greater parity was associated with resistin and leptin; however, this association was attenuated after accounting for CVD risk factors. Dysregulation of adipokines could contribute to the excess CVD risk associated with multiparity. Further studies are needed to determine whether adipokines independently mediate the relationship between multiparity and CVD. Clinical trials registration: The MESA cohort is registered at NCT00005487.

Leptin Improves Parameters of Brown Adipose Tissue Thermogenesis in Lipodystrophic Mice.

Lipodystrophy syndromes (LD) are a heterogeneous group of very rare congenital or acquired disorders characterized by a generalized or partial lack of adipose tissue. They are strongly associated with severe metabolic dysfunction due to ectopic fat accumulation in the liver and other organs and the dysregulation of several key adipokines, including leptin. Treatment with leptin or its analogues is therefore sufficient to reverse some of the metabolic symptoms of LD in patients and in mouse models through distinct mechanisms. Brown adipose tissue (BAT) thermogenesis has emerged as an important regulator of systemic metabolism in rodents and in humans, but it is poorly understood how leptin impacts BAT in LD. Here, we show in transgenic C57Bl/6 mice overexpressing sterol regulatory element-binding protein 1c in adipose tissue (Tg (aP2-nSREBP1c)), an established model of congenital LD, that daily subcutaneous administration of 3 mg/kg leptin for 6 to 8 weeks increases body temperature without affecting food intake or body weight. This is associated with increased protein expression of the thermogenic molecule uncoupling protein 1 (UCP1) and the sympathetic nerve marker tyrosine hydroxylase (TH) in BAT. These findings suggest that leptin treatment in LD stimulates BAT thermogenesis through sympathetic nerves, which might contribute to some of its metabolic benefits by providing a healthy reservoir for excess circulating nutrients.