Adiponectin, the adiponectin paradox, and Alzheimer's Disease: Is this association biologically plausible?

Dementia, especially Alzheimer's Disease (AD) and vascular dementia, is a major public health problem that continues to expand in both economically emerging and hegemonic countries. In 2017, the World Alzheimer Report estimated that over 50 million people were living with dementia globally. Metabolic dysfunctions of brain structures such as the hippocampus and cerebral cortex have been implicated as risk factors for dementia. Several well-defined metabolic risk factors for AD include visceral obesity, chronic inflammation, peripheral and brain insulin resistance, type 2 diabetes mellitus (T2DM), hypercholesterolemia, and others. In this review, we describe the relationship between the dysmetabolic mechanisms, although still unknown, and dementia, particularly AD. Adiponectin (ADPN), the most abundant circulating adipocytokine, acts as a protagonist in the metabolic dysfunction associated with AD, with unexpected and intriguing dual biological functions. This contradictory role of ADPN has been termed the adiponectin paradox. Some evidence suggests that the adiponectin paradox is important in amyloidogenic evolvability in AD. We present cumulative evidence showing that AD and T2DM share many common features. We also review the mechanistic pathways involving brain insulin resistance. We discuss the importance of the evolvability of amyloidogenic proteins (APs), defined as the capacity of a system for adaptive evolution. Finally, we describe potential therapeutic strategies in AD, based on the adiponectin paradox.

Insights Into the Controversial Aspects of Adiponectin in Cardiometabolic Disorders.

In 2016, the World Health Organization estimated that more than 1.9 billion adults were overweight or obese. This impressive number shows that weight excess is pandemic. Overweight and obesity are closely associated with a high risk of comorbidities, such as insulin resistance and its most important outcomes, including metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. Adiponectin has emerged as a salutary adipocytokine, with insulin-sensitizing, anti-inflammatory, and cardiovascular protective properties. However, under metabolically unfavorable conditions, visceral adipose tissue-derived inflammatory cytokines might reduce the transcription of the adiponectin gene and consequently its circulating levels. Low circulating levels of adiponectin are negatively associated with various conditions, such as insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular disease. In contrast, several recent clinical trials and meta-analyses have reported high circulating adiponectin levels positively associated with cardiovascular mortality and all-cause mortality. These results are biologically intriguing and counterintuitive, and came to be termed "the adiponectin paradox". Adiponectin paradox is frequently associated with adiponectin resistance, a concept related with the downregulation of adiponectin receptors in insulin-resistant states. We review this contradiction between the apparent role of adiponectin as a health promoter and the recent evidence from Mendelian randomization studies indicating that circulating adiponectin levels are an unexpected predictor of increased morbidity and mortality rates in several clinical conditions. We also critically review the therapeutic perspective of synthetic peptide adiponectin receptors agonist that has been postulated as a promising alternative for the treatment of metabolic syndrome and type 2 diabetes mellitus.

Synergistic Effect of Inflammatory Cytokines and Body Adiposity on Insulin Resistance and Endothelial Markers in Patients With Stages 3-5 Chronic Kidney Disease.

BACKGROUND: High body adiposity, inflammatory cytokines, insulin resistance (IR), and the endothelial markers-soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular adhesion molecule-1 (sVCAM-1)-are among cardiovascular risk factors observed in chronic kidney disease (CKD). Synergistic interaction of inflammatory cytokines with adiposity on IR, sICAM-1, and sVCAM-1 has not been reported in nondialysis-dependent CKD (NDD-CKD) patients. Thus the study aim was to evaluate the interaction of inflammatory cytokines on the association of body adiposity with the cardiometabolic risk factors-IR, sICAM-1, and sVCAM-1-in NDD-CKD patients. Cytokines association with estimated glomerular filtration rate (eGFR) and body adiposity was also examined. DESIGN AND METHODS: A cross-sectional study was conducted in an interdisciplinary outpatient Nephrology Clinic. SUBJECTS AND MEASUREMENTS: NDD-CKD adults with eGFR ≤60 mL/minute/1.73 m2 under regular treatment. Inflammatory cytokines, homeostasis model assessment of insulin resistance (HOMA-IR), sICAM-1, sVCAM-1, eGFR (by CKD-Epidemiology collaboration equation)-EPI equation, and body composition assessed by dual-energy X-ray absorptiometry and anthropometry were evaluated. Synergistic effects of inflammatory markers with body adiposity on studied cardiometabolic risk factors were assessed by interaction and mediation analysis. RESULTS: The study cohort comprised 241 NDD-CKD patients (54.8% men; eGFR = 29.4 ± 12.9 mL/minute/1.73 m2). Variables evaluated: Inflammatory cytokines were not associated with eGFR and not different among CKD stages. Percentage of total body adiposity (%TBA) was independently associated with tumor necrosis factor-alpha (TNFα) and HOMA-IR. Waist-to-height ratio was independently associated with TNFα, interleukin-8, monocyte chemoattractant protein-1 (MCP1), and HOMA-IR. Interaction analysis showed TNFα, interleukin-8, and MCP1 as independent mediators of the effects of high percentage of total body adiposity and waist-to-height ratio on HOMA-IR (P < .0001). Body adiposity did not associate with sICAM-1 and sVCAM-1. TNFα (ß = 0.40) and MCP1 (ß = 0.31) were independently associated with sVCAM-1 (P < .01). CONCLUSIONS: In NDD-CKD patients, inflammatory cytokines synergistically mediated the effects of body adiposity, enhancing the cardiometabolic risk. Inflammation was associated with sVCAM-1, but not with eGFR.

Clinical profiles associated with LRRK2 and GBA mutations in Brazilians with Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by remarkable phenotypic variability. Accumulated evidence points that the manifestation of PD clinical signs might be differentially modified by genetic factors, as mutations in LRRK2 and GBA genes. In this sense, the clarification of the genotype-phenotype correlations in PD has important implications in predicting prognosis and can contribute to the development of specific therapeutic approaches. METHODS: Here, we conducted the first comparative analysis of motor and non-motor features in 17 LRRK2 and 22 GBA mutation carriers and 93 non-carriers unrelated PD patients from Brazil, a highly admixed population. RESULTS: Significant differences were found between the three groups. LRRK2 PD patients presented more occurrence of familiar history. Resting tremor was observed in a lower frequency in GBA mutation carries. In contrast, gait freezing and dysautonomia was present in lower frequencies in LRRK2 carriers. Besides that, LRRK2 and GBA mutation carriers showed a higher incidence of depressive symptoms and a younger age at onset, when compared to non-carriers. CONCLUSION: Our results suggest that specific mutations in GBA and LRRK2 influence the clinical signs of the disease, with significant implications for handling of specific patient groups.

High-molecular weight adiponectin/HOMA-IR ratio as a biomarker of metabolic syndrome in urban multiethnic Brazilian subjects.

Metabolic syndrome (MetS) has an important epidemiological relevance due to its increasing prevalence and association with type 2 diabetes and cardiovascular disease. Insulin resistance is a core feature of the MetS. HOMA-IR is a robust clinical and epidemiological marker of MetS. Adiponectin is an adipokine with insulin-sensitizing and anti-inflammatory functions; its levels decrease as number of components of MetS increases. High-molecular weight adiponectin (HMWA) is the multimer responsible for the relationship of adiponectin with insulin sensitivity. HOMA-IR and HMWA are suitable candidates for MetS biomarkers. The ratio of adiponectin to HOMA-IR has been validated as a powerful index of MetS and considered a better marker of its presence, than either HOMA-IR or adiponectin alone, in selected homogeneous populations. We compared the strength of association between HMWA, HOMA-IR and HMWA/HOMA-IR ratio with MetS and its key components. Our data have shown that the median (25th, 75th percentile) of HMWA/HOMA-IR ratio was lower in subjects with MetS [0.51 (0.33, 1.31)] as compared to those without it [2.19 (1.13, 4.71)]. The correlation coefficient (r) was significantly higher for HMWA/HOMA-IR ratio as compared to HMWA for waist circumference (-0.65; -0.40, respectively); mean blood pressure (-0.27; -0.14, respectively); fasting glucose (-0.38; -0.19, respectively); HDL-cholesterol (0.44; 0.40, respectively); and triglycerides (-0.35; -0.18, respectively). In a multivariable logistic regression analysis, the HMWA/HOMA-IR ratio was a sensitive predictor for MetS, being the only marker that was significantly associated with each and all the individual components of the syndrome. These results expand on previous studies in that we used the active circulating form of adiponectin, i.e. HMWA, and represent a typical Brazilian cohort characterized by intense interethnic admixture. Thus, the HMWA/HOMA-IR ratio is a minimally invasive biomarker for MetS that could be clinically useful in prognosing patient outcome.

Vitamin D status in renal transplant recipients living in a low-latitude city: association with body fat, cardiovascular risk factors, estimated glomerular filtration rate and proteinuria.

Recent evidence suggests that vitamin D deficiency is associated with CVD, impaired kidney function and proteinuria. To date, no study has evaluated these associations in renal transplant recipients (RTR) adjusting for body adiposity assessed by a 'gold standard' method. This study aimed to evaluate the vitamin D status and its association with body adiposity, CVD risk factors, estimated glomerular filtration rate (eGFR) and proteinuria in RTR, living in Rio de Janeiro, Brazil (a low-latitude city (22°54'10"S)), taking into account body adiposity evaluated by dual-energy X-ray absorptiometry (DXA). This cross-sectional study included 195 RTR (114 men) aged 47·6 (sd 11·2) years. Nutritional evaluation included anthropometry and DXA. Risk factors for CVD were hypertension, diabetes mellitus, dyslipidaemia and the metabolic syndrome. eGFR was evaluated using the Chronic Kidney Disease Epidemiology Collaboration equation. Serum 25-hydroxyvitamin D (25(OH)D) concentration was used to define vitamin D status as follows: 10 % (n 19) had vitamin D deficiency (30 ng/ml). Percentage of body fat (DXA) was significantly associated with vitamin D deficiency independently of age, sex and eGFR. Lower 25(OH)D was associated with higher odds of the metabolic syndrome and dyslipidaemia after adjustment for age, sex and eGFR, but not after additional adjustment for body fat. Hypertension and diabetes were not related to 25(OH)D. Lower serum 25(OH)D was associated with increasing proteinuria and decreasing eGFR even after adjustments for age, sex and percentage of body fat. This study suggests that in RTR of a low-latitude city hypovitaminosis D is common, and is associated with excessive body fat, decreased eGFR and increased proteinuria.

Circulating Endocannabinoids and the Polymorphism 385C>A in Fatty Acid Amide Hydrolase (FAAH) Gene May Identify the Obesity Phenotype Related to Cardiometabolic Risk: A Study Conducted in a Brazilian Population of Complex Interethnic Admixture.

The dysregulation of the endocannabinoid system is associated with cardiometabolic complications of obesity. Allelic variants in coding genes for this system components may contribute to differences in the susceptibility to obesity and related health hazards. These data have mostly been shown in Caucasian populations and in severely obese individuals. We investigated a multiethnic Brazilian population to study the relationships among the polymorphism 385C>A in an endocannabinoid degrading enzyme gene (FAAH), endocannabinoid levels and markers of cardiometabolic risk. Fasting plasma levels of endocannabinoids and congeners (anandamide, 2-arachidonoylglycerol, N-oleoylethanolamide and N-palmitoylethanolamide) were measured by liquid chromatography-mass spectrometry in 200 apparently healthy individuals of both genders with body mass indices from 22.5 ± 1.8 to 35.9 ± 5.5 kg/m2 (mean ± 1 SD) and ages between 18 and 60 years. All were evaluated for anthropometric parameters, blood pressure, metabolic variables, homeostatic model assessment of insulin resistance (HOMA-IR), adiponectin, leptin, C-reactive protein, and genotyping. The endocannabinoid levels increased as a function of obesity and insulin resistance. The homozygous genotype AA was associated with higher levels of anandamide and lower levels of adiponectin versus wild homozygous CC and heterozygotes combined. The levels of anandamide were independent and positively associated with the genotype AA position 385 of FAAH, C-reactive protein levels and body mass index. Our findings provide evidence for an endocannabinoid-related phenotype that may be identified by the combination of circulating anandamide levels with genotyping of the FAAH 385C>A; this phenotype is not exclusive to mono-ethnoracial populations nor to individuals with severe obesity.

Repercussões de variantes genéticas em componentes do sistema endocanabinoide e no receptor PPAR-α sobre o perfil de risco cardiometabólico, adipocitocinas e níveis plasmáticos de endocanabinoides em indivíduos com diferentes graus de adiposidade / Effects of genetic variants in components of the endocannabinoid system and the PPAR-α receptor on the cardiometabolic risk profile, adipocytokines and plasma endocannabinoid levels in subjects with varying degrees of adiposity

Analisar a associação recíproca entre fatores de risco cardiometabólico, níveis de adipocitocinas (leptina e adiponectina de alto peso molecular), endocanabinoides (anandamida [AEA] e 2-araquidonoilglicerol [2-AG]), compostos canabimiméticos (N-oleoiletanolamina [OEA] e N-palmitoiletanolamina [PEA]) e polimorfismos em genes codificadores de componentes do sistema endocanabinoide (enzima de degradação de endocanabinoides FAAH [gene FAAH] e receptor endocanabinoide CB1 [gene CNR1]) e do receptor PPAR-α[genePPARA], em indivíduos com diferentes graus de adiposidade. Duzentos indivíduos, entre 18 e 60 anos, com diferentes graus de índice de massa corporal (IMC) compuseram a amostra, dividida em dois grupos: cem eutróficos (IMC < 25 kg/m2) e 100 obesos (IMC ≥30 kg/m2), com 50 homens e 50 mulheres em cada grupo. Os obesos ficaram assim distribuídos: grau 1, com IMC < 35 kg/m2(n=54), 27 homens e 27 mulheres; grau 2, com IMC < 40 kg/m2 (n=32), 16 homens e 16 mulheres e grau 3, com IMC ≥40 kg/m2(n=14), 7 homens e 7 mulheres. Todos os indivíduos foram recrutados entre funcionários, estudantes e residentes do Hospital Universitário Pedro Ernesto, bem como voluntários do quadro da Polícia Militar do Estado do Rio de Janeiro e selecionados com base em amostra de conveniência. Todos foram avaliados por parâmetros antropométricos, determinação da pressão arterial, análises laboratoriais e genotipagem, para determinar seu perfil metabólico, níveis de endocanabinoides e adipocitocinas e rastreamento dos polimorfismos FAAH385C>A, CNR13813A>G e PPARA484C>G. Foram excluídos do estudo aqueles com história de comorbidades crônicas, doenças inflamatórias agudas, dependência de drogas de qualquer natureza e em uso de medicação nos dez dias anteriores à entrada no estudo. A atividade inflamatória, avaliada pela proteína C reativa ultrassensível (PCRUS), acompanhou o grau de resistência insulínica...

To analyze the reciprocal association of cardiomet abolic risk factors, levels of adipocytokines (leptin and high molecular weight adiponectin), endocannabinoids (anandamide [AEA] and 2-arachidonoylglycerol [2-AG]), cannabimimetic compounds (N-oleoylethanolamine [OEA] and N-palmitoylethanolamine [PEA]) and polymorphisms in genes encoding components of the endocannabinoid system (endocannabinoid degradation enzyme FAAH [FAAHgene] and endocannabinoid receptor CB1 [CNR1gene]) and the PPAR-α receptor (PPARAgene) in subjects with varying degrees of adiposity. Two hundred individuals between 18 and 60 years with varying degrees of body mass index (BMI) comprised the sample, divided in two groups: one hundred eutrophic (BMI < 25 kg/m2) and 100 obese (BMI ≥30 kg/m2), 50 men and 50 women per group. The obese were distributed as follows: grade 1, with BMI < 35 kg/m2(n = 54), 27 men and 27 women; grade 2, with BMI between ≥35 and < 40 kg/m2 (n = 32), 16 men and 16 women and grade 3, with BMI ≥40 kg/m2(n = 14), 7 men and 7 women. All subjects were recruited from staff, students and residents of Pedro Ernesto University Hospital, as well as volunteers from Military Police of Rio de Janeiro State and selected based on a convenience sample. All were evaluated by anthropometric parameters, blood pressure determination, laboratory analysis and genotyping, to determine their metabolic profile, endocannabinoid and adipocytokine levels and investigate the polymorphisms FAAH385C>A, CNR1 3813G>A and PPARA484C>G. Those with a history of chronic comorbidities, acute inflammatory diseases, drug addiction of any kind and on medication in the ten days prior to study entry were withdrawn from the study.The inflammatory activity as assessed by high sensitive C reactive protein (hsCRP), accompanied the degree of insulin resistance...

Association between leptin and its soluble receptor with cardiometabolic risk factors in a Brazilian population.

BACKGROUND: Most studies evaluating the conjoint effects of leptin and human soluble leptin receptor (hs-LR) on cardiometabolic risk factors have been conducted in well-characterized ethnic groups. We aimed to assess the associations of leptin and hs-LR with the cardiometabolic risk factors that reflect the components of metabolic syndrome (MetS) in a Brazilian population with varying degrees of adiposity. METHODS: This is a cross-sectional analysis of adult subjects (n=173, age 45 ± 12 years, 124 women; body mass index [BMI] 35.6 ± 9.5 kg/m(2)) for association of leptin and its soluble receptor with cardiometabolic risk factors (glucose, BMI, waist circumference, hip circumference, blood pressure, insulin, cholesterol and triglycerides). Plasma hs-LR was measured by ELISA; insulin and leptin were determined by RIA. Metabolic syndrome was defined by NCEP/ATP III. RESULTS: Leptin was positively associated with blood pressure, BMI, waist circumference, hip circumference, triglycerides, glucose, insulin and HOMA and inversely correlated with HDL-cholesterol. The hs-LR exhibited inverse relationship with cardiometabolic risk factors (P ≤ 0.006), except for glucose and lipid parameters. Leptin increased, whereas hs-LR decreased, with increasing number of MetS components (P for trend<0.001). In multivariable models, sex, BMI and insulin were independently associated with leptin, whereas age, sex, BMI and systolic blood pressure were the independent correlates of hs-LR. CONCLUSION: In a Brazilian population with complex interethnic admixture, levels of hs-LR and leptin were independently associated with systolic blood pressure and insulin, respectively. Leptin increased with increasing number of MetS components. In turn, hs-LR decreased as the number of MetS components increased.

Psicanalise e o pensamento contemporaneo

O autor comeca com reflexoes gerais sobre o humanismo psicanalitico, assunto raramente abordado em psicanalise. Mais adiante afirma que, quando alguem inicia sua analise, na verdade esta empreendendo uma campanha pela libertacao das amarras emocionais. Para o homem situar-se na realidade, precisa divisar as perspectivas das possibilidades do nosso tempo, que se fundamentam nas concepcoes politico-economicas em vigencia, na tecnologia e sobretudo nas revelacoes da intimidade animica.

Bases psicodinamicas da delinquencia

O que me proponho e transmitir uma visao geral das motivacoes inconscientes da atividade delituosa. Quando, na abordagem da problematica da delinquencia, se atribuia a hereditariedade a causa primordial, as dissertacoes se limitavam a descricao da fenomenologia dos casos. Com o advento da Psicanalise, porem, alem dos fatores constitucionais passou-se a valorizar os fatores ambientais adversos e sobretudo, la no comeco da vida, a relacao materno-filial. Desta sorte, o estudo em profundidade do desenvolvimento da adaptacao social enriqueceu-se de achados surpreendentes.