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.

Effects of Blood Pressure Lowering Agents on Cardiovascular Outcomes in Weight Excess Patients: A Systematic Review and Meta-analysis.

BACKGROUND: Obesity hypertension is an ongoing pandemic. The first-line medications to treat this condition are still subject to debate. We compared diuretics, calcium-channel blockers (CCB), beta-blockers (BB), angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) as an initial antihypertensive therapy for prevention of cardiovascular morbimortality of hypertensive individuals who are overweight or obese. METHODS: We conducted a search of the literature for randomized clinical trials in which at least 50% of the participants were overweight or obese. The primary outcomes were all-cause mortality, cardiovascular mortality, acute myocardial infarction (MI), heart failure (HF), stroke, or end-stage renal disease. RESULTS: Our search yielded 16 randomized studies. Comparisons of two classes of drugs with at least two studies indicated that (1) CCB and ACEI increased the risk of HF [relative risk (RR) = 2.26; 95% confidence interval (CI) 1.16-4.40] and stroke [hazard ratio (HR) = 1.13; 1.00-1.26]), respectively, compared to diuretics; and (2) CCB showed a reduction in stroke (HR = 0.77; 0.66-0.89) and total mortality (HR = 0.94; 0.87-1.01) compared to the BB atenolol. Comparisons of two classes of antihypertensive medications with only one study showed that the risk of MI was higher with ARB valsartan versus CCB (HR = 1.19; 95% CI 1.02-1.38, p = 0.02). In contrast, losartan lowered the risk of a composite cardiovascular outcome compared to atenolol (HR = 0.87; 95% CI 0.77-0.98, p = 0.02). CONCLUSIONS: In hypertensive subjects with excess weight, diuretics are more effective for preventing HF and stroke than CCB and ACEI, respectively. CCB are a good first-line choice for prevention of cardiovascular disease, except HF.

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.

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.

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.

Temporal relation between body mass index and renal function in individuals with hypertension and excess body weight.

OBJECTIVE: Recent evidence has suggested obesity as an independent risk factor for chronic kidney disease. However, the temporal relation between body mass index (BMI) and early renal dysfunction is unknown. This study aimed at evaluating whether longitudinal variations in BMI would reflect on changes in estimated glomerular filtration rate (GFR) in hypertensive individuals with excess body weight. METHODS: This was a cross-sectional, longitudinal study. RESULTS: Of the 218 participants who attended the first examination, 150 were available for paired final analyses. At the end of follow-up, GFR decreased by 1.024 mL/min for each 1-kg/m(2) increment in BMI (P<0.03). When BMI was analyzed in quartiles, a positive graded relation with GFR changes was observed in quartiles 1 and 2 (individuals who maintained or lost weight), and a negative relation in quartiles 3 and 4 (individuals who gained weight, P=0.05). A significant difference was observed between the smallest and highest BMI quartiles (P=0.01). At the end of follow-up, the 76 participants (51%) who gained weight (+4.6+/-0.4 kg) showed a reduction in GFR (-2.99+/-1.99 mL/min) of borderline significance (P=0.06) and a significant increase in fasting plasma glucose and triacylglycerol levels. Conversely, the 74 participants who maintained or lost weight showed no significant change in GFR and in fasting plasma glucose and triacylglycerol levels, although their blood pressure decreased significantly. CONCLUSIONS: Our study showed a significant temporal association between changes in BMI and GFR in overweight and obese hypertensive patients.

[Effects of greater-than-5% weight reduction on hemodynamic, metabolic and neuroendocrine profiles of grade I obese subjects]. / Efeitos da redução de peso superior a 5% nos perfis hemodinâmico, metabólico e neuroendócrino de obesos grau I.

OBJECTIVE: To evaluate the effects of a greater-than-5% weight reduction in hemodynamic, metabolic, and neuroendocrine profiles of grade I obese subjects. METHODS: Observational study with 47 grade I obese subjects, with mean age of 33 years who received monthly orientation regarding diet, physical exercises, and eating behavior for four months. Blood pressure using the auscultatory method and pulse rate were assessed monthly, whereas the following variables (and respective methods) were measured at the beginning and at the end of the study: total cholesterol, triglycerides, HDL-cholesterol (enzymatic method), LDL-cholesterol (Friedewald formula), blood glucose (hexokinase method), leptin, adiponectin, renin, aldosterone, insulin (radioimmunoassay) and insulin-resistance index (HOMA). RESULTS: After adjustment for other variables, significant reductions of 6 mmHg in diastolic blood pressure, 7 pg/ml in renin, 13 mg/dl in total cholesterol and 12 mg/dl in LDL-cholesterol were observed in the greater-than-5% weight reduction group. Also, a tendency to a higher increase in adiponectin levels by the end of the study, as well as a three-fold higher reduction in blood glucose, insulin, and HOMA levels, and a six-fold higher reduction in leptin levels were observed in this group. CONCLUSION: Non-pharmacological measures that promote a greater-than-5% weight reduction produce hemodynamic, metabolic, and neuroendocrine effects that improve the cardiovascular risk of obese subjects.

Efeitos da redução de peso superior a 5 por cento nos perfis hemodinâmico, metabólico e neuroendócrino de obesos grau I / Effects of greater-than-5 percent weight reduction on hemodynamic, metabolic and neuroendocrine profiles of grade I obese subjects

OBJETIVO: Avaliar os efeitos da redução de peso superior a 5 por cento nos perfis hemodinâmico, metabólico e neuroendócrino de obesos grau I. MÉTODOS: Estudo observacional com 47 obesos grau I, média de idade de 33 anos, submetidos a orientação mensal quanto a dieta, exercício físico e comportamento alimentar, durante quatro meses. A pressão arterial, pelo método auscultatório, e a freqüência cardíaca, pelo método palpatório, foram avaliadas mensalmente, enquanto as seguintes variáveis (e respectivos métodos) foram medidas no início e final do estudo: colesterol total, triglicerídeos, HDL-colesterol (enzimático), LDL-colesterol (fórmula de Friedwald), glicemia (enzimático hexoquinase), leptina, adiponectina, renina, aldosterona, insulina (radioimunoensaio) e índice de resistência à insulina (HOMA). RESULTADOS: Observamos, após ajuste para outras variáveis, reduções significativas de 6 mmHg na pressão arterial diastólica, 7 pg/ml na renina, 13 mg/dl no colesterol total e 12 mg/dl no LDL-colesterol, no grupo com redução de peso superior a 5 por cento. Notamos, também nesse grupo, tendência ao aumento de maior magnitude da adiponectina ao final do estudo, bem como diminuição três vezes maior dos níveis de glicemia, insulina e HOMA, e seis vezes maior da leptina. CONCLUSÃO: Medidas não-farmacológicas capazes de promover redução de peso superior a 5 por cento produzem efeitos hemodinâmicos, metabólicos e neuroendócrinos que melhoram o risco cardiovascular de obesos.

p.Q223R leptin receptor polymorphism associated with obesity in Brazilian multiethnic subjects.

Several genes play a major role in obese phenotypes, and studies suggest that genetic variations among individuals, as well as their lifestyles, may bring about different body compositions. Among these genes, LEP, which codifies leptin, and the LEPR gene encoding its receptor were extensively studied for variants that could explain the obese phenotype. The LEPR p.Q223R gene polymorphism was analyzed in a sample of obese and nonobese individuals from Brazil to evaluate the role of this polymorphism in the obese phenotype in the population. Two hundred obese patients (60 males, 140 females, body mass index (BMI) >30 kg/m2) were screened, together with 150 lean or normal healthy individuals (63 males, 87 females, BMI <24 kg/m2). Genomic DNA was extracted and amplified by polymerase chain reaction (PCR). PCR products were digested with the restriction of endonuclease MspI, and separated by electrophoresis through an 8% polyacrilamide gel stained with silver nitrate. There was a significant difference in LEPR p.Q223R polymorphism frequency when comparing obese and lean subjects, with an odds ratio of 1.92 and a 95% confidence interval of 1.15-3.22 (P = 0.013). There is a strong association of the LEPR p.Q223R gene polymorphism with obesity in Brazil.

A emergência de um novo modulador cardiovascular - a 2ªenzima de conversão da angiotensina 2 (ECA2) / The emergenceof a new cardiovascular modulator 2ªangiostensin-converting enzyme 2 (ACE2)

O sistemarenina-angiotensina (SR-A) exerce um papel central no controle das várias alças de regulação cardiovascular. Muito dos seus efeitos são modulados pela enzima conversora de angiotensina (ECA) que remove dois aminoácidos da angiotensina I para formar a angiotensina II (AngII). A Ang II é o vasoconstrictor mais potente entre os que participam da fisiopatogenia da hipertensão arterial. Outros produtos do SR-A também contribuem para os mecanismos reguladores da perfusão tecidual. É o caso da angiotensina(1-7), gerada diretamente da Ang I por endopeptidases, e que é um potente vasodilatador, opondo-se às ações tróficas da Ang II. A partir de 2000, uma outra enzima do SR-A foi caracterizada; sua sequência genômica apresentou várias semelhanças estruturais com o gene da ECA humana. Por isso, foi denominada ECA2. É expressa principalmente pelas células endoteliais, coração e rim. A ECA2 tem atividades biológicas distintas da ECA, convertendo a Ang I em Ang(1-9), que é subsequentemente hidrolisada pela ECA em Ang(1-7). A ECA2 hidrolisa a Ang II, produzindo, também, a partir daí, a Ang II, produzindo, também, a partir daí, a Ang(1-7). A ECA2, além de ser uma enzima chave na geração de um potente vasodilatador [Ang(1-7)], é essencial para uma adequada função miocárdica. A perspectiva de se contar com uma droga que especificamente induza à formação de ECA2, atenuando, ao mesmo tempo, a atividade da Ang II poderá abrir novos horizontes terapêuticos para a hipertensão arterial e doenças cardiovasculares

Nefropatia diabética / Diabetic nephropathy

Diabetes mellitus é uma das principais causas de falência renal. Na presente revisäo maior ênfase é dada à nefropatia dos diabéticos do tipo 2, já que se registra um aumento exponencial desta complicaçäo da doença tanto em países afluentes como nos emergentes, à semelhança do Brasil. Os seguintes pontos säo destacados: 1- a pesquisa de microalbuminúria como elemento essencial para o diagnóstico precoce da nefropatia diabética; 2-o rígido controle de glicemia por existir estreita correlaçäo entre níveis glicêmicos e o desenvolvimento de nefropatia; 3-a manutençäo de cifras pressóricas abaixo de 130/85 mmHg para todos os diabéticos e inferior a 125/75 mmHg para aqueles com nefropatia e proteinúria acima de 1g por dia. Os inibidores da enzima de conversäo da angiotensina säo os anti-hipertensivos de primeira escolha para o tratamento da nefropatia diabética. A eficácia de outros hipotensores, como os antagonistas AT-1, também é discutida, bem como a possibilidade de tratamento combinado com ambos os agentes para propiciar um bloqueio mais eficaz do sistema renina- angiotensina. Outros aspectos da nefropatia diabética, como sua fisiopatologia, aparecem nesta revisäo.(au)

Leptina, elo adicional na fisiopatologia da pré-eclâmpsia? / Leptin, additional link to the pathophysiology of preeclampsia?

Objetivo: avaliar o comportamento dos níveis séricos de leptina durante a evolução da gestação de adolescentes primigestas normotensas e pré-eclâmpticas. Métodos: estudo prospectivo e longitudinal, realizado em 15 pacientes normotensas e 5 pré-eclâmpticas. Os níveis séricos de leptina (ng/mL) foram determinados por radioimunoensaio e a pressão arterial foi aferida pelo DINAMAP 1846. Foram feitas avaliações em dois períodos gestacionais distintos: entre a 21ª e a 30ª semana e entre a 31ª e a 40ª semana. Utilizou-se a razão leptina/índice de massa corporal (IMC) para corrigir a variação do IMC ao longo da gravidez. Considerou-se como pré-eclâmpticas as gestantes com pressão arterial ³140/90 mmHg, proteinúria >300 mg/24 h e espasmo arteriolar pelo exame de fundo de olho. Resultados: quando se comparou o período entre a 21ª a 30ª semana com o período entre a 31ª e a 40ª semana, houve tendência de aumento da leptina sérica no último período nos dois grupos estudados, mais acentuadamente nas pré-eclâmpticas que nas grávidas normotensas: de 11,9±1,59 para 17,6±4,55 ng/ml e de 11,9±1,20 para 13,9±2,33 ng/mL, respectivamente. O IMC de gestantes normotensas não se alterou nos dois períodos analisados: 24,9±1,5 kg/m² vs 25,2±1,0 kg/m². Entretanto, o IMC aumentou significativamente nas pré-eclâmpticas no final da gravidez: 21,5±0,8 vs 27,4±1,7 kg/m², p<0,05. Nas pré-eclâmpticas a razão leptina/ IMC elevou-se significativamente no final da gestação: de 0,56±0,06 (da 21ª à 30ª semana) vs 0,70±0,15 (entre 31 e 40 semanas), p<0,05. Os valores da razão leptina/ IMC de grávidas normotensas foram de 0,44±O,02 com 21 a 30 semanas vs 0,41±O,04 com 31 a 40 semanas. Nas gestantes normais a leptina se correlacionou direta e significativamente com o IMC tanto entre a 21ª a 30ªsemana (r = 0,7, p<0,004), como entre a 31ª e a 40ª semana (r=0,94, p<0,0001). Estas correlações se perderam nas pré-eclâmpticas. Conclusão: o aumento das concentrações séricas de leptina e da relação leptina/ IMC nas pré-eclâmpticas em relação às normotensas, nos dois períodos gestacionais, sugere resistência à ação da leptina na pré-eclâmpsia.