Abstract Patients with chronic renal insufficiency (CRI), also at its early stages, have an elevated risk of cardiovascular disease (CVD). Many well-established risk factors of CVD co-occur in CRI, e.g. dyslipidemia and hypertension. The present studies investigated the association between renal function and selected CVD risk factors. The fractional catabolic rate of low-density lipoprotein apolipoprotein B (LDL FCR) has previously been found to be reduced in patients with severe CRI or on dialysis. This study investigated the LDL FCR in 57 patients with moderate to severe CRI and not on dialysis. Although the mean LDL FCR was comparable between the CRI patients and healthy controls, among the renal patients the LDL FCR was correlated with renal function, whereas it was significantly reduced only in patients with advanced CRI (estimated glomerular filtration rate <15 mL/min/1.73 m2). Leptin is a protein regulating food intake and energy expenditure and it is also involved in lipid metabolism. Hyperleptinaemia is a known feature of CRI patients; they are thought to be leptin resistant. The association between leptin and the lipoprotein profile was studied in 73 CRI patients with moderate to severe CRI and not on dialysis. Leptin was associated with lipid and lipoprotein concentrations in the renal patients, as in the control subjects, pointing towards a poorer lipoprotein profile with higher leptin levels. Hypertensive subjects in whom nocturnal blood pressure (BP) declines by less than 10% (non-dippers) show more organ damage than those in whom it falls by more than 10% (dippers). Here, non-dipping was found in 19% of middle-aged subjects (226 males, 234 females) evaluated with ambulatory BP monitoring. The non-dippers had significantly lower renal function as compared with the dippers, and dipping status was a significant predictor of the variation in eGFR. Furthermore, an increased risk of non-dipping was observed among subjects with only minor decreases in renal function. Carotid intima-media thickness (cIMT) can be used as a surrogate marker of early atherosclerosis. The present study investigated the association between renal function and cIMT in middle-aged subjects (247 males, 258 females). Renal function was independently associated with cIMT among males and also among postmenopausal women. The increased cIMT was seen in conjunction with mild renal impairment. In conclusion, the catabolism of LDL correlated with the renal function among CRI patients, but it was significantly reduced only in patients with advanced CRI. Leptin concentrations correlated with the lipoprotein profile in CRI patients. Among general middle-aged subjects, even a mild decrease in renal function was associated with derangements in BP regulation and with increased carotid atherosclerosis.

Abstract The semi-domesticated reindeer is a northern species of Cervidae that is exposed to extreme seasonal changes in temperature and nutrition in its living environment. The objective of this study was to examine the significance of thermogenic brown adipose tissue (BAT) for the survival of newborn reindeer in the cold during the critical perinatal period. The other main objective was to study the effect of wintertime undernutrition on serum and bone marrow fatty acid composition in yearling reindeer, with particular attention on the proportions of unsaturated and polyunsaturated fatty acids (PUFAs) and their feasibility as indicators of nutritional status. The results showed that the most of the adipose tissues in newborn reindeer were functionally active BAT. The tissue had specific anatomical locations, specialized cell morphological structure, high aerobic capacity, and tissue-specific mitochondrial 32000 Mr-uncoupling protein (UCP1) that is considered a rate-limiting factor for thermogenesis. The most readily mobilized fatty acids from BAT triacylglycerols were arachidonic, linoleic, and α-linolenic acids. BAT was most active at birth and during the close perinatal period but its aerobic capacity declined during the first month of life while UCP1 disappeared and the tissue gradually adopted the histological characteristics of white adipose tissue. The newborn reindeer had very low proportions of the principal C18-PUFAs, linoleic and α-linolenic acids, in serum lipids. However, the proportions of C18-PUFAs increased during the first few days of life by a rate that suggests a selective retention of these fatty acids from milk lipids. A prolonged restricted feeding of reindeer with lichen during winter and spring induced significant reductions in the proportions of linoleic and α-linolenic acids in serum cholesteryl esters and phospholipids, while proportion of arachidonic acid and serum prostaglandin PGF2α metabolite concentration increased. Plasma leptin and insulin levels decreased in parallel with decreases in feed intake and body weight. In freely ranging reindeer, the proportions of oleic acid and principal C18-PUFAs were significantly reduced in femur bone marrow triacylglycerols as a result of a wintertime undernutrition. In conclusion, active BAT is the dominant adipose tissue type in the newborn reindeer and it is likely to have a major significance on the thermoregulatory heat production and cold resistance of reindeer during the perinatal period. The changes in the specific PUFA proportions of serum and bone marrow lipids refleict the changes in the nutritional status and suggest that these fatty acids are preferentially utilized during prolonged wintertime undernutrition.

Metabolic homeostasis is orchestrated by the hypothalamus through the neuroendocrine and the autonomic nervous systems. The hypothalamic nuclei respond to the peptide leptin secreted from adipose tissue to suppress feeding and increase energy expenditure by promoting fat metabolism via sympathetic activity. Another important, but perhaps less appreciated function of central leptin signaling is to elevate peripheral insulin sensitivity. Environmental and genetic risk factors that affect hypothalamic leptin signaling can lead to obesity and type 2 diabetes mellitus (T2DM). Here, we discovered that LIM domain only 4, LMO4, is a novel protein participating in central leptin signaling. In a process strikingly similar to T2DM in humans, CaMKIIα-Cre;LMO4flox/flox mice, which have LMO4 knocked out in the postnatal brain including the hypothalamus, develop visceral adiposity, reduced insulin sensitivity, obesity and diabetes when fed with regular chow. Central leptin signaling was significantly lost in key hypothalamic nuclei of mutant mice. Caloric restriction prevents obesity but not insulin resistance in these mice. Taken together, our results suggest that LMO4 function in the brain is required for central leptin signaling to control fat metabolism and peripheral insulin sensitivity.

Orientador: Ricardo de Lima Zollner / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-07T21:49:59Z (GMT). No. of bitstreams: 1 Gontijo_BrunaAguiar_M.pdf: 901672 bytes, checksum: 6bc049b20d4924d05f816322f4e366f8 (MD5) Previous issue date: 2005 / Resumo: A Leptina é um hormônio produzido principalmente pelo tecido adiposo, estudos sugerem sua relação com o aumento do processo inflamatório observado no diabetes mellitus tipo 1 (DM-1) em camundongos NOD (diabético não obeso), modelo experimental desta doença. Neste estudo, analisou-se o efeito da leptina sobre a viabilidade das células em cultura e na expressão de citocinas pro-inflamatórias (TNFa, IFN?, IL1ß, IL-12 e IL-2) por RT-PCR. Além disso, analisou-se a resposta induzida pela leptina em cultura de células esplênicas, após o estímulo in vivo com adjuvante Completo de Freund (CFA). Os resultados sugerem que a leptina modula a expressão de citocinas pro-inflamatórias, sendo esta modulação específica para cada citocina estudada, sem relação dose dependência, mas de acordo com a resposta imunológica desencadeada pelo efeito do CFA em camundongos NOD e Balb-C / Abstract: Leptin is a hormone produced mainly by the adipocites, studies suggest that can be related with the inflammatory process in type 1 Diabetes (IDDM) observed in NOD mice (diabetic non-obese), a classic experimental model of autoimmune diabetes. In this study, we analyze the leptin effect on cell culture viability and pro-inflammatory cytokines expression in NOD and BALB-C mice spleen cells. The spleen cells were cultivated 24, 48 and 72 hours with different leptin concentrations and the pro-inflammatory cytokines expression (TNFa, IFN?, IL1ß, IL-2, IL-12) were addressed by RT-PCR. Furthermore, we studied the leptin-induced spleen cell response in culture, after in vivo Complete Freund Adjuvant (CFA) stimulation. Our results suggest that leptin can modulates the proinflammatory cytokines expression without relation to dependent on the dose but in accordance with the status of immune response promoted by CFA effect in Balb-C and NOD mice / Mestrado / Ciencias Basicas / Mestre em Clinica Medica

Obesity is a major risk factor for insulin resistance, type 2 diabetes, cardiovascular disease (CVD), and vascular calcification. Vascular calcification is correlated with advanced CVD and a significant predictor of cardiovascular events. Obese individuals tend to have increased levels of circulating leptin, an adipocytokine that is a significant independent predictor of cardiovascular disease. We have shown that daily intraperitoneal injections of exogenous leptin (125 μg/mouse/d) can promote vascular calcification in an ApoE-/- mouse model of atherosclerosis. This increase in calcification is associated with an increase in the expression of several osteoblast-specific markers and is independent of any affect on atherosclerotic lesion size. Our studies suggest that leptin mediates the osteogenic differentiation of vascular smooth muscle cells (VSMCs) to promote vascular calcification via a pathway involving the inhibition of glycogen synthase kinase (GSK)-3 activity. Other studies have suggested that endoplasmic reticulum (ER) stress-induced GSK-3 activity promotes the development of atherosclerosis. Therefore, we hypothesized that during the progression of vascular disease, GSK-3 functions as a checkpoint for VSMCs at which cells can commit to: i) de-differentiation, thereby contributing to atherosclerosis, or ii) osteogenic differentiation, thereby contributing to vascular calcification. We investigated the effects of modulating GSK-3 activity on the differentiation of VSMCs in vitro. We found that many of the molecular tools that are typically used to modulate ER stress can promote the expression of osteoblast-specific markers and the osteogenic differentiation of MOVAS cells. However, because many of these interventions affect multiple pathways in MOVAS cells, the specific role of the ER stress – GSK-3 pathway is difficult to discern. Future studies are required to determine the effects of direct modulation of GSK-3 on vascular calcification and to delineate the mechanisms/effects of various ER stressors in the osteogenic differentiation of VSMCs. / Thesis / Doctor of Philosophy (Medical Science)

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Experiments were conducted to evaluate nitric oxide (NO) involvement in the leptin effect on food intake in both broiler and Leghorn chickens. The first experiment studied the effect of leptin combined with L-arginine on the food intake in broilers. Intracerebroventricular (ICV) administration of human recombinant leptin injection decreased (P=.01) food intake from 15 to 150 minutes compared to the control group treated with artificial cerebrospinal fluid ( aCSF) while food intake was increased by L-arginine. Food intake between the group receiving leptin and L-arginine was similar to the control group. Therefore, broilers were sensitive to the anoregenic effects of leptin, while L-arginine, a NO precursor appeared to attenuate the leptin effect on food intake. The effect of leptin and L-NNA on food intake in broilers was measured in the second experiment. Lepin, L-NNA and leptin plus L-NNA decreased food intake. The NO inhibitor L-NNA tended to enhance the suppression of leptin on food intake. In the third experiment, using Leghorns instead of broilers, the ICV injection of leptin decreased food intake from 15 to 60 minutes postinjection (P=.05). However, food intake was not affected by injection of L-arginine plus leptin. Therefore, L-arginine appeared to antagonize the leptin inhibitory effect on food intake. A small increase food intake induced by L-arginine was also observed (P=.09). The change of food intake in Leghorns administered leptin and L-NNA were measured in Experiment 4. Food intake was decreased by L-NNA and leptin with the effects lasting 60 minutes, similar to that observed in broilers (P<0.0l). For group B (leptin treatment), there was decreased food intake within 45 minutes (P=.04) and the effect disappeared 60 minutes, post injection. Also, the results along with Experiment 2 demonstrated that NO mediated the effect of leptin in Leghorns. The fifth experiment investigated the change in concentration of metabolites of nitric oxide after injection of leptin within 30 minutes. The group treated with the leptin had a lower level of metabolites of nitric oxide in the hypothalamus than the control group (P=.004). This effect further demonstrates that leptin modulated feeding activity through its inhibition on nNOS activity in the hypothalamus. These results showed that both leptin and NO participated in the regulation of food intake in broiler and Leghorn chickens, and the effect of hypothalamic neuropeptidergic circuitry leptin on food intake was mediated by NO. / Master of Science

Truncal adiposity impairs ventilation in obese adults by altering normal ventilatory mechanics. Leptin, an inflammatory adipocytokine, is elevated in obesity and has been shown to alter ventilatory responses to exercise. Leptin’s bioavailability appears to be regulated by its soluble receptor (LRe), which is reduced in obesity. Roux-en-Y gastric bypass surgery (RYGBS) is a weight loss intervention that reduces total fat mass and improves several obesity related co-morbidities including pulmonary dysfunction. The purpose of this study was to first evaluate the differences between ventilatory responses to carbon dioxide (VE/VCO2 slope) during progressive treadmill walking in morbidly obese and normal weight females. Second, we will analyze the relationships between the VE/VCO2 slope, truncal adiposity, serum leptin, and LRe. Lastly, we want to evaluate the changes in the ventilatory responses to exercise (VE/VCO2 slope), truncal adiposity, serum leptin, and LRe 3 months following Roux-en Y gastric bypass surgery. Thirteen obese (OB 37.7 ±11.4 years, 42.0 ± 4.8 kg/m2) and 12 normal weight females (NW 36.1 ±8.0 years, 22.8 ± 1.2 kg/m2) participated in this study. Blood samples for measure of fasting serum leptin and soluble leptin receptor were obtained prior to exercise. Cardiopulmonary variables were measured throughout exercise. Regional adiposity was determined through dual energy x-ray absorptiometry. Truncal adiposity was significantly greater in the obese group than the normal weight group. Serum leptin was greater in the obese group while LRe was lower than the normal weight group. The VE/VCO2 slopes were lower in obese group when compared to the normal weight group. There were no significant group differences in maximal ventilation, tidal volume or respiratory rate. Stepwise regression determined that truncal adiposity accounted for 31.5% of variance in VE/VCO2 slope (R= 0.561, R2 =0.315, p = 0.004). At 3 months post-surgery we observed significant reductions in the obese group in total percentages of fat, truncal adiposity, serum leptin. The soluble leptin receptor was not changed at any measured time point following RYGBS. There were no changes in 3 months post-surgery VE/VCO2 slopes in the obese group. Truncal adiposity, serum leptin and LRe were associated with reduced ventilatory responses to weight bearing exercise (VE/VCO2 slope) in obese females when compared to normal weight females. There were no differences between obese and normal weight females in maximal minute ventilation, tidal volume or respiratory rate. This result suggests that differences in VE/VCO2 slopes may not be entirely from maximal pulmonary capacity. Rather, the differences in VE/VCO2 slope may be attributed to truncal adiposity and its positive relationship with leptin. Elevated leptin in the obese group may indicate a state of central leptin resistance which has been shown to reduce the ventilatory responses to exercise. At 3 months post RYGBS significant reductions in total percent fat, serum leptin, truncal adiposity and BMI were observed. However, despite improvement in fat mass and serum leptin there were no changes in the VE/VCO2 slope and LRe at 3 months post RYGBS. Therefore, it is possible that the improvements in body composition and leptin following RYGBS were not sufficient to increase ventilation responses to weight bearing exercise in obese females.