Adipokines, the bioactive factors derived mainly from adipocytes, regulate pancreatic beta-cell function including insulin secretion, gene expression and apoptosis. In this review, we propose that adipokines influence beta-cell function through three interdependent pathways. The first is through regulating lipid and glucose metabolism in beta-cells. The second implicates the change of ion channel opening and closing in beta-cells. The third pathway is via the modification of insulin sensitivity of beta-cells. The endocrine function of adipocytes is dynamic, and the secretion of various adipokines changes under different metabolic conditions. During the progression from the normal state to obesity and to type 2 diabetes, adipokines contribute to the occurrence and development of beta-cell dysfunction in type 2 diabetes.
Adipocytes ; physiology ; Adiponectin ; physiology ; Animals ; Diabetes Mellitus, Type 2 ; physiopathology ; Glucose ; metabolism ; Humans ; Insulin ; pharmacology ; Insulin-Secreting Cells ; physiology ; Leptin ; physiology ; Lipid Metabolism

Accumulating evidence suggests that obesity is associated with chronic pain. However, whether obesity is associated with acute inflammatory pain is unknown. Using a well-established obese mouse model induced by a high-fat diet, we found that: (1) the acute thermal pain sensory threshold did not change in obese mice; (2) the model obese mice had fewer nociceptive responses in formalin-induced inflammatory pain tests; restoring the obese mice to a chow diet for three weeks partly recovered their pain sensation; (3) leptin injection induced significant phosphorylation of STAT3 in control mice but not in obese mice, indicating the dysmodulation of topical leptin-leptin receptor signaling in these mice; and (4) leptin-leptin receptor signaling-deficient mice (ob/ob and db/db) or leptin-leptin receptor pathway blockade with a leptin receptor antagonist and the JAK2 inhibitor AG 490 in wild-type mice reduced their nociceptive responses in formalin tests. These results indicate that leptin plays a role in nociception induced by acute inflammation and that interference in the leptin-leptin receptor pathway could be a peripheral target against acute inflammatory pain.
Animals ; Diet, High-Fat ; adverse effects ; Inflammation ; chemically induced ; metabolism ; Leptin ; metabolism ; pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Nociception ; drug effects ; physiology ; Nociceptive Pain ; etiology ; metabolism ; Obesity ; complications ; metabolism ; Pain Measurement ; Pain Threshold ; drug effects ; physiology ; Receptors, Leptin ; metabolism ; Signal Transduction ; drug effects ; physiology

PURPOSE: Obesity is a major risk factor for asthma and it influences airway smooth muscle function and responsiveness. Adiponectin is inversely associated with obesity and its action is mediated through at least 2 cell membrane receptors (AdipoR1 and AdipoR2). Leptin is positively associated with obesity. We investigated whether human airway smooth muscle (ASM) cells express adiponectin receptors and whether adiponectin and leptin regulate human ASM cell proliferation and vascular endothelial growth factor (VEGF) release. MATERIALS AND METHODS: Human ASM cells were growth-arrested in serum-deprived medium for 48 hours and then stimulated with PDGF, adiponectin and leptin. After 48 hours of stimulation, proliferation was determined using a cell proliferation ELISA kit. Human AdipoR1 and -R2 mRNA expressions were determined by RT-PCR using human-specific AdipoR1 and -R2 primers. Concentrations of VEGF, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1alpha in cell culture supernatant were determined by ELISA. RESULTS: Both AdipoR1 and AdipoR2 mRNA were expressed in the cultured human ASM cells. However, adiponectin did not suppress PDGF-enhanced ASM cell proliferation, nor did leptin promote ASM cell proliferation. Leptin promoted VEGF release by human ASM cells, while adiponectin did not influence VEGF release. Neither leptin nor adiponectin influenced MCP-1 secretion from human ASM cells. Adiponectin and MIP-1alpha were not secreted by human ASM cells. CONCLUSION: Human ASM cells expressed adiponectin receptors. However, adiponectin did not regulate human ASM cell proliferation or VEGF release, while leptin stimulated VEGF release by human ASM cells.
Adiponectin/metabolism/*pharmacology/physiology ; Cell Proliferation/*drug effects ; Cells, Cultured ; Chemokine CCL2/metabolism ; Chemokine CCL3/metabolism ; Humans ; Leptin/metabolism/*pharmacology/physiology ; Myocytes, Smooth Muscle/cytology/drug effects/*metabolism ; Obesity/metabolism ; Platelet-Derived Growth Factor/metabolism ; Receptors, Adiponectin/*metabolism ; Respiratory System/cytology/metabolism ; Vascular Endothelial Growth Factor A/metabolism

OBJECTIVETo investigate the regulation of leptin on insulin secretion and expression of ATP-sensitive potassium channel subunit sulfonulurea receptor 1 (SUR1) mRNA, and to determine whether the effects of leptin are mediated through known intracellular signaling transduction.

METHODSPancreatic islets were isolated by the collagenase method from male SD rats. The purified islets were incubated with different concentrations of leptin for 2 h in the presence of different concentrations of glucose. Insulin release was measured using radioimmunoassay. Expression of SUR1 mRNA was detected by RT-PCR.

RESULTSIn the presence of leptin 2 nmol/L, insulin release was significantly inhibited at either 11.1 or 16.7 mmol/L glucose concentration (both P < 0.05), but insulin release was not altered at glucose of 5.6 mmol/L physiological concentration. The dose-response experiment showed that the maximal effect of leptin on insulin secretion achieved at 2 nmol/L. Exposure of islets to 2 nmol/L leptin induced a significant increase of SUR1 transcription levels by 71% (P < 0.01) at 11.1 mmol/L glucose and by 56% (P < 0.05) at 16.7 mmol/L glucose concentration. Selective phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin significantly prevented the leptin effect on insulin secretion and SUR1 mRNA expression.

CONCLUSIONSRegulatory effects of leptin on insulin secretion could be biphasic at different concentrations of glucose and leptin. The stimulatory regulation of SUR1 transcription levels may be mediated through activation of PI 3-kinase pathway, which may be a possible mechanism of leptin in regulating insulin secretion.

Animals ; Butadienes ; pharmacology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Insulin ; secretion ; Islets of Langerhans ; drug effects ; metabolism ; Leptin ; pharmacology ; Male ; Nitriles ; pharmacology ; Phosphatidylinositol 3-Kinases ; physiology ; Potassium Channels, Inwardly Rectifying ; genetics ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley

Leptin is an adipocytokine that regulates body weight, and maintains energy homeostasis by promoting reduced food intake and increasing energy expenditure. Leptin expression and secretion is regulated by various factors including hormones and fatty acids. Butyrate is a short-chain fatty acid that acts as source of energy in humans. We determined whether this fatty acid can play a role in leptin expression in fully differentiated human adipocytes. Mature differentiated adipocytes were incubated with or without increasing concentrations of butyrate. RNA was extracted and leptin mRNA expression was examined by Northern blot analysis. Moreover, the cells were incubated with regulators that may affect signals which may alter leptin expression and analyzed with Northern blotting. Butyrate stimulated leptin expression, and stimulated mitogen activated protein kinase (MAPK) and phospho-CREB signaling in a time-dependent manner. Prior treatment of the cells with signal transduction inhibitors as pertusis toxin, Gi protein antagonist, PD98059 (a MAPK inhibitor), and wortmannin (a PI3K inhibitor) abolished leptin mRNA expression. These results suggest that butyrate can regulate leptin expression in humans at the transcriptional level. This is accomplished by: 1) Gi protein-coupled receptors specific for short-chain fatty acids, and 2) MAPK and phosphatidylinositol-3-kinase (PI3K) signaling pathways.
Adipocytes/*metabolism ; Azo Compounds ; Butyric Acid/*pharmacology ; CREB-Binding Protein/genetics/metabolism ; Cell Differentiation ; Cells, Cultured ; Gene Expression Regulation/*drug effects/physiology ; Humans ; Leptin/genetics/*metabolism ; Mitogen-Activated Protein Kinase Kinases/genetics/metabolism ; Phosphatidylinositol 3-Kinases/genetics/metabolism ; RNA, Messenger/genetics/metabolism ; Signal Transduction/*physiology ; Staining and Labeling

This study aimed to determine whether taurine supplementation improves metabolic disturbances and diabetic complications in an animal model for type 2 diabetes. We investigated whether taurine has therapeutic effects on glucose metabolism, lipid metabolism, and diabetic complications in Otsuka Long-Evans Tokushima fatty (OLETF) rats with long-term duration of diabetes. Fourteen 50-week-old OLETF rats with chronic diabetes were fed a diet supplemented with taurine (2%) or a non-supplemented control diet for 12 weeks. Taurine reduced blood glucose levels over 12 weeks, and improved OGTT outcomes at 6 weeks after taurine supplementation, in OLETF rats. Taurine significantly reduced insulin resistance but did not improve beta-cell function or islet mass. After 12 weeks, taurine significantly decreased serum levels of lipids such as triglyceride, cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol. Taurine significantly reduced serum leptin, but not adiponectin levels. However, taurine had no therapeutic effect on damaged tissues. Taurine ameliorated hyperglycemia and dyslipidemia, at least in part, by improving insulin sensitivity and leptin modulation in OLETF rats with long-term diabetes. Additional study is needed to investigate whether taurine has the same beneficial effects in human diabetic patients.
Adipokines/blood ; Animals ; Blood Glucose ; Diabetes Mellitus, Type 2/drug therapy ; Dietary Supplements ; Dyslipidemias/blood/*drug therapy ; Glucose Tolerance Test ; Hyperglycemia/blood/*drug therapy ; Hypoglycemic Agents/administration & dosage/*pharmacology ; Hypolipidemic Agents/administration & dosage/*pharmacology ; Insulin/physiology/secretion ; Insulin Resistance ; Insulin-Secreting Cells/physiology/secretion ; Leptin/*blood ; Lipid Metabolism/drug effects ; Lipids/blood ; Male ; Organ Specificity ; Rats ; Rats, Long-Evans ; Taurine/administration & dosage/*pharmacology

Adipose tissue is an important endocrine regulator of glucose metabolism and energy homeostasis. Researches have focused on this tissue not only as a target for pharmacotherapy of obesity and insulin resistance but also as an endocrine tissue with leptin secretion and high insulin sensitivity. Brown adipose tissue (BAT) additionally plays a unique role in thermoregulation through the mitochondrial uncoupling protein 1 (UCP1), which uncouples oxidative phosphorylation. As a genetic tissue ablation model of BAT, we made transgenic mice expressing herpes simplex virus thymidine kinase (HSV-TK) driven by the brown adipocyte- specific UCP1 minimal regulatory element. The HSV-TK transgene was expressed specifically in BAT and more than 35% increase of apoptosis was induced by ganciclovir (GCV) treatment. Nevertheless, the expression level was not high enough to induce BAT ablation in GCV-treated adult mice. Importantly, however, we found that brown adipocytes in the periphery of interscapular BAT were transformed into white adipocyte-like unilocular cells. These cells express white adipocyte-specific leptin protein but are different in the ultrastructure of mitochondria from classical white adipocytes. Our data indicates that atrophy of BAT causes transformation into white adipocyte-like cells in the adult mouse and also suggests that further molecular understanding of adipocyte plasticity using our transgenic mouse model might be beneficial for the development of anti-obesity/anti-diabetic therapies.
Adipose Tissue/*cytology/drug effects/metabolism/ultrastructure ; Aging/physiology ; Animals ; Body Weight ; Carrier Proteins/genetics/metabolism ; *Cell Differentiation/drug effects ; Ganciclovir/pharmacology ; Ion Channels ; Leptin/metabolism ; Membrane Proteins/genetics/metabolism ; Mice ; Mice, Transgenic ; Mitochondrial Proteins ; Obesity/chemically induced ; Organ Specificity ; Thymidine Kinase/genetics/metabolism