Peroxisome proliferator-activated receptors (PPAR) belong to the nuclear receptor superfamily of ligand-activated transcription factors. PPAR-α
, first of its three subtypes (α, β, γ) has traditionally been considered an important regulator of lipid metabolism while its role in the regulation of insulin sensitivity has not been recognized until recently. Here we summarize the experimental and clinical studies focusing on the role of PPAR-α in the regulation of insulin sensitivity. In most of the experimental studies the activation of PPAR-α in rodents leads to improvement of insulin sensitivity by multiple mechanisms including improvement of insulin signaling due to a decrease of ectopic lipids in
non-adipose tissues and decrease of circulating fatty acids and triglycerides
. In contrast, the effect of PPAR-α agonist in humans is much less pronounced probably due to a lower expression of PPAR-α relative to rodents and possibly other mechanisms. Further clinical studies using more potent PPAR-α agonists on a larger population need to be performed to
evaluate the possible role of PPAR-α in the regulation of insulin sensitivity in humans.
Leptin is a 16 kDa protein hormone involved in food intake, energy expenditure regulation and numerous other physiological processes. Recently, leptin has been demonstrated to stimulate hematopoietic stem cells in vitro. The aim of our study was to measure serum leptin and erythropoietin levels in patients with sideropenic (n =18) and pernicious anemia (n=7) before and during anemia treatment. Blood samples for the blood count, leptin and erythropoietin determinations were obtained by venepunction at the time of the diagnosis of anemia and after partial and complete anemia recovery. The relationships of serum leptin levels to erythropoietin levels and blood count parameters were also studied. No significant differences in serum leptin levels between the groups studied were found. The serum leptin levels in none of groups were modified by treatment of anemia (basal levels, the levels during treatment and after anemia recovery were 13.1±14.5 vs 12.8±15.6 vs 12.0±14.8 ng/ml in patients with sideropenic anemia and 7.8±8.5 vs 9.5±10.0 vs 8.9±6.6 ng/ml in patients with pernicious anemia). The erythropoietin levels were higher at the time of anemia in both groups and decreased significantly after partial or complete recovery. Serum leptin levels in both groups correlated positively with the body mass index. No significant relationships were found between serum leptin levels and erythropoietin values or various parameters of the peripheral blood count. We conclude that serum leptin levels in patients with sideropenic and pernicious anemia positively correlate with the body mass index but are not influenced by the treatment of anemia., M. Marková, M. Haluzík, J. Svobodová, M. Rosická, J. Nedvídková, T. Haas., and Obsahuje bibliografii
Adipocyte hormone leptin (OB protein) is considered to be an "adiposity signal" regulating body weight homeostasis and energy balance. We have previously reported that oestrogens (oestradiol-benzoate) significantly decrease the body weight in male rats, increase anterior pituitary and serum levels of the intracellular messenger cAMP, which activates cAMP-dependent protein kinase A , their targets include hormone-sensitive lipase and they influence the brain sympathetic system. The present study tested our hypothesis that oestrogens could influence serum leptin levels in male mice. We found that chronic administration of oestradiol-benzoate significantly attenuated serum levels of leptin, in the dependence on the duration of its administration, and simultaneously decreased body weight. We suppose that oestrogens affect leptin levels interacting with the signal transmission system of cAMP, possibly at the genome level. Our observations that the food consumption of mice with simultaneously decreased body weight and levels of serum leptin support the idea that there exists a satiety factor that counters the effect of low leptin.
Mitochondrial dysfunction is a potentially important player in the development of insulin resistance and type 2 diabetes mellitus (T2DM). We investigated the changes of mRNA expression of genes encoding main enzymatic complexes of mitochondrial respiratory chain in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) of 11 subjects with simple obesity (OB), 16 obese patients with T2DM and 17 healthy lean subjects (C) before and after very low-calorie diet (VLCD) using quantitative real time PCR. At baseline in SCAT, both T2DM and OB group had decreased mRNA expression of all investigated mitochondrial genes with the exception of 2 complex I (NDUFA 12) and complex IV (COX 4/1) enzymes in OB subjects. In contrast, in PM only the expression of complex I enzymes NDUFA 12 and MT-ND5 was reduced in both T2DM and
OB subjects along with decreased expression of citrate synthase (CS) in T2DM group. Additionally, T2DM subjects showed reduced activity of pyruvate dehydrogenase and complex IV in peripheral blood elements. VLCD further decreased mRNA expression of CS and complex I (NT-ND5) and II (SDHA) enzymes in SCAT and complex IV (COX4/1) and ATP synthase in PM of T2DM group, while increasing the activity of complex IV in their peripheral blood elements. We conclude that impaired mitochondrial biogenesis and decreased activity of respiratory chain enzymatic complexes was present in SCAT and PM of obese and diabetic patients. VLCD improved metabolic parameters and ameliorated mitochondrial oxidative function in peripheral blood elements of T2DM subjects but had only minor and inconsistent effect on mitochondrial gene mRNA expression in SCAT and PM.
The excessive production of nitric oxide (NO) and the subsequent increase of local oxidative stress is suggested as one of the pathophysiological mechanisms of streptozotocin-induced diabetes. It was reported that the administration of NO synthase inhibitors partially attenuated the development of streptozotocin-induced diabetes and reduced hyperglycaemia. Here we have studied the influence of methylene blue, which combines the properties of NO synthase inhibitor with antioxidant effects. The experiments were performed on male rats divided into four groups: control, diabetic (single dose of 70 mg of streptozotocin/kg i.p.), methylene blue (50 mg/kg in the food) and diabetic simultaneously fed with methylene blue. After 45 days the experiments were discontinued by decapitation. Serum glycaemia, glycated haemoglobin and oxidative stress parameters (plasma malondialdehyde concentration and erythrocyte superoxide dismutase activity) were significantly higher in the diabetic group. Simultaneous methylene blue administration partially reduced glycaemia and glycated haemoglobin, but did not decrease oxidative stress. We conclude that NO synthase inhibitor methylene blue partially attenuates the development of streptozotocin-induced diabetes in male rats, but does not reduce the development of oxidative stress in the diabetic group.
The aim of our study was to determine whether adipocyte-derived hormones leptin, adiponectin and resistin contribute to the improvement of insulin sensitivity after very-low calorie diet (VLCD). Therefore, serum levels of these hormones were measured in fourteen obese females before and after three weeks VLCD and in seventeen age- and sex-matched healthy controls. Body mass index, HOMA index, serum insulin and leptin levels in obese women before VLCD were significantly higher than in control group (BMI 48.01±2.02 vs. 21.38±0.42 kg/m2, HOMA 10.72±2.03 vs. 4.69±0.42, insulin 38.63±5.10 vs. 18.76±1.90 μIU/ml, leptin 77.87±8.98 vs. 8.82±1.52 ng/ml). In contrast, serum adiponectin and soluble leptin receptors levels were significantly lower in obese women before VLCD than in the control group. No differences were found in serum glucose and resistin levels between the obese group before VLCD and the control group. VLCD significantly decreased BMI, HOMA index, serum glucose, insulin and leptin levels and increased soluble leptin receptor levels. The changes in serum adiponectin and resistin levels in obese women after VLCD did not reach statistical significance. We conclude that leptin and soluble leptin receptor levels were affected by VLCD while adiponectin and resistin concentrations were not. Therefore, other mechanisms rather than changes in the endocrine function of the adipose tissue are probably involved in the VLCD-induced improvement of insulin sensitivity.