Altered Body Composition and Increased Resting Metabolic Rate Associated with the Postural Instability/Gait Difficulty Parkinson’s Disease Subtype

Background. Weight loss in Parkinson’s disease (PD) patients is a common but poorly understood manifestation. Several studies have reported that weight changes could be related to motor symptoms, drug side effects, dysphagia, depression, and/or dementia. Weight loss in PD is not a benign phenomenon and it has several clinical and prognostic implications with increased morbidity and mortality. Thus, it is crucial to determine nutritional changes in PD patients in order to prevent malnutrition and improve their quality of life. Objective. To compare body composition and resting metabolic rates between PD patients and controls. Methods. A total of 64 PD patients and 52 controls were studied. The Hoehn-Yahr scale was used to determine the disease stage, clinical and epidemiological data were recorded from verbal questionnaire, Inbody S10® was used to collect corporal parameters, and FitMate system was used to assess the resting metabolic rate. Results. No significant differences were found between both experimental groups in age, gender, height, cholesterol levels, and the presence of hypertension, diabetes, and hypo/hyperthyroidism. However, the PD group showed lower body fat mass, whole-body fat percentage, and greater resting metabolic rate compared to controls (p<0.05), with no significant differences in musculoskeletal mass. Parkinson’s disease postural instability/gait difficulty (PD-PIGD) subtype showed lower body fat parameters, increased fat-free mass, and higher resting metabolic rates. Conclusions. These results suggest that PD patients present an increased resting metabolic rate associated with the postural instability/gait difficulty PD subtype, allowing a selective decrease of body fat mass and not musculoskeletal mass. Of note, several disease-related factors may contribute to this weight loss in PD patients, being a complex and multifactorial consequence. Our findings could likely be one of the many contributing factors. However, present findings may further add to our understanding of the phenomenon of weight loss in patients with PD

Partial IGF-1 deficiency is sufficient to reduce heart contractibility, angiotensin II sensibility, and alter gene expression of structural and functional cardiac proteins.

Circulating levels of IGF-1 may decrease under several circumstances like ageing, metabolic syndrome, and advanced cirrhosis. This reduction is associated with insulin resistance, dyslipidemia, progression to type 2 diabetes, and increased risk for cardiovascular diseases. However, underlying mechanisms between IGF-1 deficiency and cardiovascular disease remain elusive. The specific aim of the present work was to study whether the partial IGF-1 deficiency influences heart and/or coronary circulation, comparing vasoactive factors before and after of ischemia-reperfusion (I/R). In addition, histology of the heart was performed together with cardiac gene expression for proteins involved in structure and function (extracellular matrix, contractile proteins, active peptides); carried out using microarrays, followed by RT-qPCR confirmation of the three experimental groups. IGF-1 partial deficiency is associated to a reduction in contractility and angiotensin II sensitivity, interstitial fibrosis as well as altered expression pattern of genes involved in extracellular matrix proteins, calcium dynamics, and cardiac structure and function. Although this work is descriptive, it provides a clear insight of the impact that partial IGF-1 deficiency on the heart and establishes this experimental model as suitable for studying cardiac disease mechanisms and exploring therapeutic options for patients under IGF-1 deficiency conditions

Effect of Ethanol Consumption on the Placenta and Liver of Partially IGF-1-Deficient Mice: The Role of Metabolism via CYP2E1 and the Antioxidant Enzyme System

Ethanol use during pregnancy is a risk factor for developing adverse outcomes. Its metabolism by cytochrome P450 2E1 (CYP2E1) produces radical oxygen species (ROS), promoting cellular injury and apoptosis. To date, no studies have been conducted to elucidate the teratogenic effects due to both IGF-1 deficiency and ethanol consumption in mice placentas. The aim of this study is to determine the effect of ethanol consumption on the placenta and liver of partially IGF-1-deficient mice, the role of metabolism via CYP2E1, and the antioxidant enzyme system. Heterozygous (HZ, Igf1+/−) pregnant female mice were given water or 10% ethanol. Wild-type (WT, Igf1+/+) female mice were used as controls. At gestational day 19, pregnant dams were euthanized, and maternal liver and placentas were collected. Pregnant HZ dams were smaller than controls, and this effect was higher due to ethanol consumption. Cyp2e1 gene was overexpressed in the liver of HZ pregnant dams exposed to ethanol; at the protein level, CYP2E1 is reduced in placentas from all genotypes. The antioxidant enzymatic system was altered by ethanol consumption in both the maternal liver and placenta. The results in this work hint that IGF-1 is involved in intrauterine development because its deficiency exacerbates ethanol’s effects on both metabolism and the placenta

IGF-1 modulates gene expression of proteins involved in inflammation, cytoskeleton, and liver architecture

Even though the liver synthesizes most of circulating IGF-1, it lacks its receptor under physiological conditions. However, according to previous studies, a damaged liver expresses the receptor. For this reason, herein, we examine hepatic histology and expression of genes encoding proteins of the cytoskeleton, extracellular matrix, and cell-cell molecules and inflammation-related proteins. A partial IGF-1 deficiency murine model was used to investigate IGF-1’s effects on liver by comparing wild-type controls, heterozygous igf1+/−, and heterozygous mice treated with IGF-1 for 10\ua0days. Histology, microarray for mRNA gene expression, RT-qPCR, and lipid peroxidation were assessed. Microarray analyses revealed significant underexpression of igf1 in heterozygous mice compared to control mice, restoring normal liver expression after treatment, which then normalized its circulating levels. IGF-1 receptor mRNA was overexpressed in Hz mice liver, while treated mice displayed a similar expression to that of the controls. Heterozygous mice showed overexpression of several genes encoding proteins related to inflammatory and acute-phase proteins and underexpression or overexpression of genes which coded for extracellular matrix, cytoskeleton, and cell junction components. Histology revealed an altered hepatic architecture. In addition, liver oxidative damage was found increased in the heterozygous group. The mere IGF-1 partial deficiency is associated with relevant alterations of the hepatic architecture and expression of genes involved in cytoskeleton, hepatocyte polarity, cell junctions, and extracellular matrix proteins. Moreover, it induces hepatic expression of the IGF-1 receptor and elevated acute-phase and inflammation mediators, which all resulted in liver oxidative damage. © 2017, The Author(s)

qPCR-RT measurement of RNA (cDNA) expression of genes encoding proteins closely related to IGF-1 function.

<p>*p<0.05, ** p 0.01 vs. controls (Wt group). <b>(A)</b> <i>Igf1;</i> <b>(B), (C), (D), (E), (F)</b> <i>Igfbp3</i>, <i>4</i>, <i>5</i>, and, 7, respectively; <b>(G)</b> <i>Ctgf/Igfbp8</i>. n = 10, each group.</p

Altered expression of genes encoding proteins closely related to IGF1 physiology.

<p>Altered expression of genes encoding proteins closely related to IGF1 physiology.</p

Hemodynamic values in perfused hearts from the three experimental groups.

<p>dP/dt (mmHg/s), expressing left ventricular contractility, before and after I/R. Before I/R IGF-1 deficient mice showed a reduction of dP/dt but did not reach statistical significance, whereas Hz+IGF-1 mice presented quite similar values to controls (Wt mice). After, I/R, hearts from controls showed a significant reduction in contractility (dP/dt) and similar results were observed in hearts from Hz+IGF-1 group. However, no response after I/R was found in untreated IGF-1 deficient mice (p = ns). ## p<0.01 controls after I/R vs before I/R; # p<0.05 Hz+IGF-1 after I/R vs the same group before I/R (n = 5 each group).</p

Expression of genes encoding proteins involved on inflammation, extracellular matrix regulation, and in heart metabolism.

<p>Expression of genes encoding proteins involved on inflammation, extracellular matrix regulation, and in heart metabolism.</p

Coronary vasoconstriction to Ang II.

<p><b>(A)</b> Coronary perfusion pressure (mmHg) in hearts from the three experimental groups, at different concentrations (10⁻¹⁰ to 10⁻⁷) of Ang II before Ischemia/Reperfusion: Ang II induced vasoconstriction dose-dependent on perfused hearts from controls and Hz+IGF-1, increasing coronary perfusion pressure. However, no effect was observed after Ang II injection in hearts from Hz group. <b>(B)</b> Coronary perfusion pressure after I/R: vasoconstriction to Ang II was reduced both in controls and Hz+IGF-1 group. But no response was observed in untreated Hz group, showing a quite total insensibility to AngII (n = 5 per group). * p<0.05 Hz vs Controls; £ p<0.05 after vs. before I/R in the same group (control or Hz+IGF-1).</p

Hemodynamic values in perfused hearts from controls, mice with IGF-1 deficiency (Hz) and Hz treated with IGF-1 therapy.

<p>Hemodynamic values in perfused hearts from controls, mice with IGF-1 deficiency (Hz) and Hz treated with IGF-1 therapy.</p