Autophagy is an important process that regulates cellular homeostasis by degrading dysfunctional proteins, organelles and lipids. In this study, the hypothesis that obesity could lead to impairment in hypothalamic autophagy in mice was evaluated by examining the hypothalamic distribution and content of autophagic proteins in animal with obesity induced by 8 or 16 weeks high fat diet to induce obesity and in response to intracerebroventricular injections of palmitic acid. The results showed that chronic exposure to a high fat diet leads to an increased expression of inflammatory markers and downregulation of autophagic proteins. In obese mice, autophagic induction leads to the downregulation of proteins, such as JNK and Bax, which are involved in the stress pathways. In neuron cell- line, palmitate has a direct effect on autophagy even without inflammatory activity. Understanding the cellular and molecular bases of overnutrition is essential for identifying new diagnostic and therapeutic targets for obesity.
In both human and experimental obesity, inflammatory damage to the hypothalamus plays an important role in the loss of the coordinated control of food intake and energy expenditure. Upon prolonged maintenance of increased body mass, the brain changes the defended set point of adiposity, and returning to normal weight becomes extremely difficult. Here we show that in prolonged but not in short-term obesity, the ubiquitin/proteasome system in the hypothalamus fails to maintain an adequate rate of protein recycling, leading to the accumulation of ubiquitinated proteins. This is accompanied by an increased colocalization of ubiquitin and p62 in the arcuate nucleus and reduced expression of autophagy markers in the hypothalamus. Genetic protection from obesity is accompanied by the normal regulation of the ubiquitin/proteasome system in the hypothalamus, whereas the inhibition of proteasome or p62 results in the acceleration of body mass gain in mice exposed for a short period to a high-fat diet. Thus, the defective regulation of the ubiquitin/proteasome system in the hypothalamus may be an important mechanism involved in the progression and autoperpetuation of obesity.
Some flavonoids identified in beet stalks can help the antioxidant endogenous defenses during a chronic inflammation process. The current study investigates the effect of polyphenols present in beet stalks and leaves on liver oxidative damage in mice fed a high-fat diet (HF). The control (CT) or HF diet groups were supplemented with dehydrated beet stalks and leaves (SL) or beet stalk and leaf ethanolic extract (EX). In terms of Vitexin-rhaminoside equivalents (VRE), EX groups received ~5.91 mg of VRE·100 g−1 diet, while the SL groups received ~3.07 mg VRE·100 g−1 diet. After 8 weeks, we evaluated fasting blood glucose; cholesterol, hepatic Malondialdehyde (MDA) levels and hepatic Glutathione (GSH), Glutathione peroxidase (GPx), Glutathione reductase (GR) and Superoxide dismutase (SOD) activity. Dehydrated beet stalks and leaves (HFSL) attenuated the deleterious effects of a HF diet on lipid metabolism, reduced fasting blood glucose levels, ameliorated cholesterol levels and reduced GPx and GR activities (p < 0.05) compared to the HF group. However; the addition of ethanolic extract from beet stalks and leaves was unable (p > 0.05) to prevent the liver damage caused by HF diet in mice. The presence of flavonoids, such as Vitexin derivatives in beet stalks and leaves can help the liver damage induced by HF diet.
BackgroundCrohn’s disease (CD) is associated with complex pathogenic pathways involving defects in apoptosis mechanisms. Recently, mesenteric adipose tissue (MAT) has been associated with CD ethiopathology, since adipose thickening is detected close to the affected intestinal area. However, the potential role of altered apoptosis in MAT of CD has not been addressed.AimsTo evaluate apoptosis in the intestinal mucosa and MAT of patients with CD.MethodsSamples of intestinal mucosa and MAT from patients with ileocecal CD and from non-inflammatory bowel diseases patients (controls) were studied. Apoptosis was assessed by TUNEL assay and correlated with the adipocytes histological morphometric analysis. The transcriptional and protein analysis of selected genes and proteins related to apoptosis were determined.ResultsTUNEL assay showed fewer apoptotic cells in CD, when compared to the control groups, both in the intestinal mucosa and in MAT. In addition, the number of apoptotic cells (TUNEL) correlated significantly with the area and perimeter of the adipose cells in MAT. Transcriptomic and proteomic analysis reveal a significantly lower transcript and protein levels of Bax in the intestinal mucosa of CD, compared to the controls; low protein levels of Bax were found localized in the lamina propria and not in the epithelium of this tissue. Furthermore, higher level of Bcl-2 and low level of Caspase 3 were seen in the MAT of CD patients.ConclusionThe defective apoptosis in MAT may explain the singular morphological characteristics of this tissue in CD, which may be implicated in the pathophysiology of the disease.
Crohn's disease (CD) is a chronic inflammatory disorder, characterized by cytokine imbalance and transcription signaling pathways activation. In addition, the increase of mesenteric adipose tissue (MAT) near the affected intestinal area is a hallmark of CD. Therefore, we evaluated the transcription signaling pathways and cytokines expression in intestinal mucosa and MAT of active CD patients. Ten patients with ileocecal CD and eight with noninflammatory diseases were studied. The biopsies of intestinal mucosa and MAT were snap-frozen and protein expression was determined by immunoblotting. RNA levels were measured by qPCR. The pIkB/IkB ratio and TNFα level were significantly higher in intestinal mucosa of CD when compared to controls. However, STAT1 expression was similar between intestinal mucosa of CD and controls. Considering the MAT, the pIkB/IkB ratio was significantly lower and the anti-inflammatory cytokine IL10 was significantly higher in CD when compared to controls. Finally, the protein content of pSTAT1 was higher in MAT of CD compared to controls. These findings reinforce the predominance of the proinflammatory NF-kB pathway in CD intestinal mucosa. For the first time, we showed the activation of STAT1 pathway in MAT of CD patients, which may help to understand the physiopathology of this immune mediated disease.
Children with cerebral palsy have feeding difficulties that can contribute to undernutrition. The aim of this study was to investigate the effect of early undernutrition on locomotor activity and the expression of the myofibrillar protein MuRF-1 in an experimental model of cerebral palsy (CP). In order to achieve this aim, pregnant rats were divided into two groups according to the diet provided: Normal Protein (NP, n=9) and Low Protein (LP, n=12) groups. After birth, the pups were divided into four groups: Normal Protein Sham (NPS, n=16), Normal Protein Cerebral Palsy (NPCP, n=21), Low Protein Sham (LPS, n=20) and Low Protein Cerebral Palsy (LPCP, n=18) groups. The experimental cerebral palsy protocol consisted of two episodes of anoxia at birth and during the first days of life. Each day, nitrogen flow was used (9l/min during 12min). After nitrogen exposure, sensorimotor restriction was performed 16h per day, from the 2nd to the 28th postnatal day (PND). Locomotor activity was evaluated at 8th, 14th, 17th, 21th and 28th PND. At PND 29, soleus muscles were collected to analyse myofibrillar protein MuRF-1. Our results show that CP animals decreased body weight (p<0.001), which were associated with alterations of various parameters of locomotor activity (p<0.05), compared to their control. Undernourished animals also showed a decrease (p<0.05) in body weight and locomotor activity parameters. Moreover, CP decreased MuRF-1 levels in nourished rats (p=0.015) but not in undernourished rats. In summary, perinatal undernutrition exacerbated the negative effects of cerebral palsy on locomotor activity and muscle atrophy, but it appears not be mediated by changes in MuRF-1 levels.
Obesity is linked with altered microbial short-chain fatty acids (SCFAs), which are a signature of gut dysbiosis and inflammation. In the present study, we investigated whether tributyrin, a prodrug of the SCFA butyrate, could improve metabolic and inflammatory profiles in diet-induced obese mice. Mice fed a high-fat diet for eight weeks were treated with tributyrin or placebo for another six weeks. We show that obese mice treated with tributyrin had lower body weight gain and an improved insulin responsiveness and glucose metabolism, partly via reduced hepatic triglycerides content. Additionally, tributyrin induced an anti-inflammatory state in the adipose tissue by reduction of Il-1β and Tnf-a and increased Il-10, Tregs cells and M2-macrophages. Moreover, improvement in glucose metabolism and reduction of fat inflammatory states associated with tributyrin treatment were dependent on GPR109A activation. Our results indicate that exogenous targeting of SCFA butyrate attenuates metabolic and inflammatory dysfunction, highlighting a potentially novel approach to tackle obesity.
Total retocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgery of choice for patients with ulcerative colitis (UC) that are refractory to clinical treatment. Pouchitis is one of the most common complications after this procedure. Defects in autophagy have been reported in inflammatory bowel diseases. However, there are no studies on the IP. Therefore, we studied markers for autophagy in the IP mucosa of UC and FAP patients comparing them to controls with a normal distal ileum. Sixteen patients with IP in "J" shape, asymptomatic and with endoscopically normal IP were evaluated. The control group consisted of eight patients with normal colonoscopy. There was a significant decrease in the transcriptional levels of ATG5, MAP1LC3A and BAX in the FAP group. There was also a decrease in the protein level of Beclin-1 in the UC and FAP compared to the control group. Although the LC3II levels by immunoblot were higher in the UC group, LC3/p62 co-localization were lower in the immunofluorescence analysis in the UC and FAP compared to the control group. Corroborating these results, there was an increase of p62 by immunoblot in the UC group. These findings indicated a modulation of macroautophagy markers in the IP, which may explain the mucosa inflammation predisposition.Ulcerative colitis (UC) is a chronic intestinal inflammation that can affect the large intestine and rectum. Its etiology is not completely established. Familial adenomatous polyposis (FAP) is an autosomal dominant disease which affects young individuals and is associated with the formation of multiple polyps in the large intestine and rectum, which invariably implies a greater risk of cancer 1,2 . Both diseases, despite being different, may require the same surgical procedure. The ileal pouch-anal anastomosis (IPAA) is the elective procedure of choice in the surgical management of refractory UC, and FAP with many polyps in the rectum 3 . The main complication after this procedure is the pouch inflammation (pouchitis) that can affect up to 45 percent of patients who are submitted to IPAA for UC, and only five percent of the FAP patients who undergo the same procedure 4 . This suggests that constitutive differences between UC and FAP pouches have a critical role in its pathogenesis.Pouchitis develops only after ileostomy closure, when the pouch mucosa starts to be exposed to the fecal stream 5 . The distinct immunological aspects of the different inflammatory bowel diseases (IBD), specifically UC, which involve impaired innate and adaptive responses, associated to genetic susceptibility, environmental factors, and intestinal microbiota may be involved in the pouch inflammation etiology 5,6 . Autophagy is an evolutionarily conserved catabolic pathway that consists of selective degradation of cellular components and a homeostatic mechanism that protects cells exposed to stress situations (toxins, starvation) 7,8 . There are three primary forms of authophagy: macroautophagy, microautophagy and chaperone-mediated autophagy (CMA) 9 . Although there ar...
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