Hypoadiponectinemia is the important cause of insulin resistance. Recent studies have shown that periodontitis is associated with hypoadiponectinemia. The purpose of this study was to investigate the effect of periodontitis-induced endoplasmic reticulum stress (ERS) in visceral adipocytes on hypoadiponectinemia.
Rat periodontitis models were established by local ligation with silk around the bilateral maxillary second molars. Porphyromonas gingivalis-lipopolysaccharid (P.g-LPS) was also used to stimulate the visceral adipocytes in vitro. The protein expression levels of glucose regulated protein 78 (GRP78), inositol-requiring protein 1α (IRE1α), protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6) and adiponectin were detected. IRE1α lentiviruses were transfected into visceral adipocytes in vitro, and an IRE1α inhibitor (KIRA6) was injected in epididymal adipose tissue of rats to detect and verify the effect of ERS on adiponectin expression in visceral adipocytes in vivo.
Hypoadiponectinemia was observed in periodontitis rat, and the expression levels of ERS key proteins GRP78 and the phosphorylation levels of IRE1α (p-IRE1α)/IRE1α in visceral adipocytes were increased, while the expression levels of adiponectin protein were decreased. After KIRA6 injection into epididymal adipose tissue of rats with periodontitis, adiponectin levels in visceral adipocytes increased, and serum adiponectin levels recovered to a certain extent. The protein expression levels of GRP78 and p-IRE1α/IRE1α were increased and adiponectin protein expression was decreased in P.g-LPS-induced visceral adipocytes. Overexpression of IRE1α further inhibited adiponectin expression in P.g-LPS-stimulated visceral adipocytes, and conversely, IRE1α inhibition restored adiponectin expression.
Our findings suggest that periodontitis induces ERS in visceral adipocytes leading to hypoadiponectinemia. IRE1α is a key protein regulating adiponectin expression in visceral adipocytes.

OBJECTIVE: Little is known about the association between plasma adiponectin levels and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). We examined whether there is an association between lower plasma adiponectin levels and the presence/severity of NAFLD in people with T2DM.
METHODS: We cross-sectionally recruited 79 men with non-insulin-treated T2DM and no known liver diseases, who had consecutively attended our diabetes outpatient service over a 6-month period and who underwent both ultrasonography and Fibroscan-measured liver stiffness (LSM). Nine single nucleotide polymorphisms (PNPLA3 rs738409 and other genetic variants) associated with NAFLD were investigated.
RESULTS: Among the 79 participants included (mean age 67 ± 10 years, BMI 27.7 ± 4 kg/m2), 28 did not have NAFLD, 32 had steatosis alone, and 19 had NAFLD with coexisting significant fibrosis (LSM ≥ 7.0 kPa by Fibroscan®). Compared to those without NAFLD, patients with hepatic steatosis alone and those with hepatic steatosis and coexisting significant fibrosis had lower high-molecular-weight adiponectin levels (5.5 [IQR 2.3-7.6] vs. 2.4 [1.8-3.7] vs. 1.6 [1.0-2.9] µg/mL; p < 0.001). After adjustment for age, body mass index, insulin resistance, and the PNPLA3 rs738409 variant, lower plasma adiponectin levels were found to be associated with increased odds of both steatosis alone (adjusted-odds ratio [OR] 2.44, 95% CI 1.04-5.56, p = 0.042) and NAFLD with coexisting significant fibrosis (adjusted-OR 3.84, 95% CI 1.23-10.0, p = 0.020). Similar findings were observed after adjustment for the other eight genotyped NAFLD-related polymorphisms.
CONCLUSIONS: Lower plasma adiponectin levels are closely associated with the presence and severity of NAFLD in men with T2DM, pointing to a role of adiponectin in NAFLD development and progression.

Metabolic syndrome (MS) is a complex pathology characterized by visceral adiposity, insulin resistance, arterial hypertension, and dyslipidaemia. It has become a global epidemic associated with increased consumption of high-calorie, low-fibre food and sedentary habits. Some of its underlying mechanisms have been identified, with hypoadiponectinemia, inflammation and oxidative stress as important factors for MS establishment and progression. Alterations in adipokine levels may favour glucotoxicity and lipotoxicity which, in turn, contribute to inflammation and cellular stress responses within the adipose, pancreatic and liver tissues, in addition to hepatic steatosis. The multiple mechanisms of MS make its clinical management difficult, involving both non-pharmacological and pharmacological interventions. Transient receptor potential (TRP) channels are non-selective calcium channels involved in a plethora of physiological events, including energy balance, inflammation and oxidative stress. Evidence from animal models of disease has contributed to identify their specific contributions to MS and may help to tailor clinical trials for the disease. In this context, the oxidative stress sensors TRPV1, TRPA1 and TRPC5, play major roles in regulating inflammatory responses, thermogenesis and energy expenditure. Here, the interplay between these TRP channels and oxidative stress in MS is discussed in the light of novel therapies to treat this syndrome.

White adipocyte adiponectin exocytosis is triggered by cAMP and a concomitant increase of cytosolic Ca2+ potentiates its release. White adipose tissue is richly innervated by sympathetic nerves co-releasing noradrenaline (NA) and ATP, which may act on receptors in the adipocyte plasma membrane to increase cAMP via adrenergic receptors and Ca2+ via purinergic receptors. Here we determine the importance of NA and ATP for the regulation of white adipocyte adiponectin exocytosis, at the cellular and molecular level, and we specifically detail the ATP signalling pathway. We demonstrate that tyrosine hydroxylase (enzyme involved in catecholamine synthesis) is dramatically reduced in inguinal white adipose tissue (IWAT) isolated from mice with diet-induced obesity; this is associated with diminished levels of NA in IWAT and with a reduced ratio of high-molecular-weight (HMW) to total adiponectin in serum. Adiponectin exocytosis (measured as an increase in plasma membrane capacitance and as secreted product) is triggered by NA or ATP alone in cultured and primary mouse IWAT adipocytes, and enhanced by a combination of the two secretagogues. The ATP-induced adiponectin exocytosis is largely Ca2+-dependent and activated via purinergic P2Y2 receptors (P2Y2Rs) and the Gq11/PLC pathway. Adiponectin release induced by the nucleotide is abrogated in adipocytes isolated from obese and insulin-resistant mice, and this is associated with ∼70% reduced abundance of P2Y2Rs. The NA-triggered adiponectin exocytosis is likewise abolished in \"obese adipocytes\", concomitant with a 50% lower gene expression of beta 3 adrenergic receptors (β3ARs). An increase in intracellular Ca2+ is not required for the NA-stimulated adiponectin secretion. Collectively, our data suggest that sympathetic innervation is a principal regulator of adiponectin exocytosis and that disruptions of this control are associated with the obesity-associated reduction of circulating levels of HMW/total adiponectin.

Ovarian cancer has been emerged as a most common and lethal gynecological malignancy in India. High serum insulin and low adiponectin have been associated with increased risk of ovarian cancer. But their role in development of ovarian cancer is conflicting and little evidence is available. We aimed to evaluate blood levels of insulin and adiponectin in epithelial ovarian cancer (EOC) patients and their association with the risk to develop EOC. The study included following three groups; Group 1: fifty cases of cytohistopathologically confirmed cases of EOC, Group 2: fifty age matched cases of benign ovarian conditions and Group 3: fifty ages matched healthy controls with no evidence of any benign or malignant ovarian pathology as ruled out by clinical examination and relevant investigations. Cytohistopathologically confirmed and newly diagnosed cases of EOC and benign ovarian cancer were included in this study. The median value of fasting serum insulin was significantly high (15.0 µlU/ml, P = 0.02) and adiponectin were significantly low (5.1 µg/ml, P < 0.001) in ovarian cancer patients compared to benign ovarian tumors and healthy controls group. A significant increase risk of ovarian cancer was found in high tertile (≥ 18.7 µlU/ml) of serum insulin level (OR = 2.7; 95% CI = 1.00-6.67, P = 0.04) and lower tertile (≤ 5.45 µg/ml) of adiponectin level (OR = 3.2; 95% CI = 1.10-9.71, P = 0.03). High serum insulin level and low adiponectin levels were significantly associated with increased risk for development of ovarian cancer.

The landmark discoveries of leptin and adiponectin firmly established adipose tissue as a sophisticated and highly active endocrine organ, opening a new era of investigating adipose-mediated tissue crosstalk. Both obesity-associated hyperleptinemia and hypoadiponectinemia are important biomarkers to predict cardiovascular outcomes, suggesting a crucial role for adiponectin and leptin in obesity-associated cardiovascular disorders. Normal physiological levels of adiponectin and leptin are indeed essential to maintain proper cardiovascular function. Insufficient adiponectin and leptin signaling results in cardiovascular dysfunction. However, a paradox of high levels of both leptin and adiponectin is emerging in the pathogenesis of cardiovascular disorders. Here, we (1) summarize the recent progress in the field of adiponectin and leptin and its association with cardiovascular disorders, (2) further discuss the underlying mechanisms for this new paradox of leptin and adiponectin action, and (3) explore the possible application of partial leptin reduction, in addition to increasing the adiponectin/leptin ratio as a means to prevent or reverse cardiovascular disorders.

Our previous data suggest that the heterodimeric interleukin-27 (IL-27) could participate in the developing of insulin resistance (IR). Our aim was to assess the participation of IL-27p28 gene single nucleotide polymorphisms (SNPs) as markers for IR, subclinical atherosclerosis (SA) and cardiovascular risk factors in a Mexican population. Five IL-27p28 SNPs (rs153109, rs40837, rs17855750, rs26528 and rs181206) were genotyped in 856 individuals with IR and 644 participants without IR. Under inheritance models adjusted for confounding factors, the rs153109A (0.78[0.64-0.94] Padditive = 0.008, 0.58[0.41-0.82] Precessive = 0.002, 0.57[0.38-0.83] Pcodominant2 = 0.004), rs26528T (0.78[0.64-0.94] Padditive = 0.008, 0.61[0.43-0.88] Precessive = 0.007, 0.57[0.38-0.84] Pcodominant2 = 0.004) and rs40837A (0.76[0.63-0.92] Padditive = 0.004; 0.60[0.42-0.86] Precessive = 0.005; 0.54[0.37-0.80] Pcodominant2 = 0.002) alleles were related with a decreased risk of IR. Moreover, AAATA haplotype that contains the protector alleles was related with 17% lower risk of presenting IR (0.83 [0.71-0.98], P = 0.023). After adjusting for potential confounding variables, IL-27p28 SNPs were not associated with SA. However, some SNPs were associated with hypertension (rs26528 and rs40837) and increased total abdominal fat (rs17855750) in non-IR individuals, whereas in IR subjects we observed an association of rs26528 and rs40837 with hypoadiponectinemia. Our evidence suggests that rs40837A, rs153109A, and rs26528T alleles could be envisaged as protective markers for IR. Some polymorphisms showed an association with hypertension, low adiponectin levels, and increased total abdominal fat.

Hypoadiponectinemia is characterized by low plasma adiponectin levels that can be caused by genetic factors, such as single nucleotide polymorphisms (SNPs) and mutations in the adiponectin gene or by visceral fat deposition/obesity. Reports have suggested that hypoadiponectinemia is associated with dyslipidemia, hypertension, hyperuricemia, metabolic syndrome, atherosclerosis, type 2 diabetes mellitus and various cardiovascular diseases. Previous studies have highlighted several potential strategies to up-regulate adiponectin secretion and function, including visceral fat reduction through diet therapy and exercise, administration of exogenous adiponectin, treatment with peroxisome proliferator-activating receptor gamma (PPARγ) agonists (e.g., thiazolidinediones (TZDs)) and ligands (e.g., bezafibrate and fenofibrate) or the blocking of the renin-angiotensin system. Likewise, the up-regulation of the expression and stimulation of adiponectin receptors by using adiponectin receptor agonists would be an effective method to treat obesity-related conditions. Notably, adiponectin is an abundantly expressed bioactive protein that also exhibits a wide spectrum of biological properties, such as insulin-sensitizing, anti-diabetic, anti-inflammatory and anti-atherosclerotic activities. Although targeting adiponectin and its receptors has been useful for treating diabetes and other metabolic-related diseases in experimental studies, current drug development based on adiponectin/adiponectin receptors for clinical applications is scarce, and there is a lack of available clinical trial data. This comprehensive review discusses the strategies that are presently being pursued to harness the potential of adiponectin up-regulation. In addition, we examined the current status of drug development and its potential for clinical applications.

Adiponectin is a protein synthesized and secreted predominantly by adipocytes into the peripheral blood. However, circulating adiponectin level is inversely related with body weight, especially visceral fat accumulation. The mechanism of this paradoxical relation remains obscure. Low circulating adiponectin concentrations (hypoadiponectinemia; <4 μg/mL) are associated with a variety of diseases, including dysmetabolism (type 2 diabetes, insulin resistance, hypertension, dyslipidemia, metabolic syndrome, hyperuricemia), atherosclerosis (coronary artery disease, stroke, peripheral artery disease), sleep apnea, non-alcoholic fatty liver disease, gastritis and gastro-esophageal reflux disease, inflammatory bowel diseases, pancreatitis, osteoporosis, and cancer (endometrial cancer, postmenopausal breast cancer, leukemia, colon cancer, gastric cancer, prostate cancer). On the other hand, hyperadiponectinemia is associated with cardiac, renal and pulmonary diseases. This review article focuses on the significance of adiponectin as a clinical biomarker of obesity-related diseases. Routine measurement of adiponectin in patients with lifestyle-related diseases is highly recommended.

OBJECTIVE: To investigate the genetic association of eight variants of the adiponectin gene with type 2 diabetes mellitus (T2DM), obesity and serum adiponectin level in the south Indian population.
METHODS: The study comprised of 1100 normal glucose tolerant (NGT) and 1100 type 2 diabetic, unrelated subjects randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), in southern India. Fasting serum adiponectin levels were measured by radioimmunoassay. The variants were screened by polymerase chain reaction-restriction fragment length polymorphism. Linkage disequilibrium was estimated from the estimates of haplotype frequencies.
RESULTS: Of the 8 variants, four SNPs namely, +276 G/T (rs1501299), -4522 C/T (rs822393), -11365 C/G (rs266729), and +712 G/A (rs3774261) were significantly associated with T2DM in our study population. The -3971 A/G (rs822396) and -11391 G/A (rs17300539) SNPs\' association with T2DM diabetes was mediated through obesity (where the association with type 2 diabetes was lost after adjusting for BMI). There was an independent association of +276 G/T (rs1501299) and -3971 A/G (rs822396) SNPs with generalized obesity and +349 A/G (rs2241767) with central obesity. Four SNPs, -3971 A/G (rs822396), +276 G/T (rs1501299), -4522 C/T (rs822393) and Y111H T/C (rs17366743) were significantly associated with hypoadiponectinemia. The haplotypes GCCATGAAT and AGCGTGGGT conferred lower risk of T2DM in this south Indian population.
CONCLUSIONS: The adiponectin gene variants and haplotype contribute to the genetic risk towards the development of type 2 diabetes, obesity and hypoadiponectinemia in the south Indian population.