Obesity and insulin resistance are the major predisposing factors to comorbidities, such as Type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular and neurodegenerative diseases, and ...several types of cancer. The prevalence of obesity is still increasing worldwide and now affects a large number of individuals. Here, we review the role of the gut microbiota in the pathophysiology of insulin resistance/obesity. The human intestine is colonized by ∼100 trillion bacteria, which constitute the gut microbiota. Studies have shown that lean and overweight rodents and humans may present differences in the composition of their intestinal flora. Over the past 10 years, data from different sources have established a causal link between the intestinal microbiota and obesity/insulin resistance. It is important to emphasize that diet-induced obesity promotes insulin resistance by mechanisms independent and dependent on gut microbiota. In this review, we present several mechanisms that contribute to explaining the link between intestinal flora and insulin resistance/obesity. The LPS from intestinal flora bacteria can induce a chronic subclinical inflammatory process and obesity, leading to insulin resistance through activation of TLR4. The reduction in circulating SCFA may also have an essential role in the installation of reduced insulin sensitivity and obesity. Other mechanisms include effects of bile acids, branched-chain amino acids (BCAA), and some other lesser-known factors. In the near future, this area should open new therapeutic avenues for obesity/insulin resistance and its comorbidities.
Thiazolidinediones (TZDs) enhanced body weight (BW) partially by increased adipogenesis and hyperphagia. Neuronal PPARγ knockout mice on high-fat diet (HFD) are leaner because of enhanced leptin ...response, although it could be secondary to their leanness. Thus, it still is an open question how TZDs may alter energy balance. Multiple factors regulate food intake (FI) and energy expenditure (EE), including anorexigenic hormones as insulin and leptin. Nonetheless, elevated hypothalamic AMPK activity increases FI and TZDs increase AMPK activity in muscle cells. Thus, the aim of the present study was to investigate whether Pioglitazone (PIO) treatment alters hypothalamic insulin and leptin action/signaling, AMPK phosphorylation, and whether these alterations may be implicated in the regulation of FI and EE.
Swiss mice on HFD (2 months) received PIO (25 mg kg(-1) per day-gavage) or vehicle for 14 days. AMPK and AdipoR1 were inhibited via Intracerebroventricular injections using Compound C (CompC) and small interference RNA (siRNA), respectively. Western blot, real-time PCR and CLAMS were done.
PIO treatment increased BW, adiposity, FI, NPY mRNA and decreased POMC mRNA expression and EE in HFD mice. Despite higher adiposity, PIO treatment improved insulin sensitivity, glucose tolerance, decreased insulin and increased adiponectin serum levels. This result was associated with, improved insulin and leptin action/signaling, decreased α2AMPK(Ser491) phosphorylation and elevated Acetyl-CoA carboxylase and AMPK(Thr172) phosphorylation in hypothalamus. The inhibition of hypothalamic AMPK with CompC was associated with decreased adiposity, FI, NPY mRNA and EE in PIO-treated mice. The reduced expression of hypothalamic AdipoR1 with siRNA concomitantly with PIO treatment reverted PIO induced obesity development, suggesting that adiponectin may be involved in this effect.
These results demonstrated that PIO, despite improving insulin/leptin action in hypothalamus, increases FI and decreases EE, partially, by activating hypothalamic adiponectin/AdipoR1/AMPK axis. Suggesting a novel mechanism in the hypothalamus by which TZDs increase BW.
To investigate whether the Cdc2-like kinase 2 (CLK2) is expressed in hypothalamic neurons and if it is, whether the hypothalamic CLK2 has a role in the regulation of energy balance.
Swiss mice on ...chow or high-fat diet (HFD) and db/db mice on chow diet were used to address the role of CLK2 in the hypothalamus.
Hypothalamic CLK2
phosphorylation, which induces CLK2 activity, is regulated in vivo by refeeding, insulin and leptin, in a PI3K (phosphoinositide 3-kinase)-dependent manner. The reduction of CLK2 expression in the hypothalamus, by chronic pharmacological inhibition with TG003 or by chronic knockdown with small interfering RNA was sufficient to abolish the anorexigenic effect of insulin and leptin, to increase body weight, fat mass, food intake and to decrease energy expenditure in mice on chow. In contrast, CLK2
phosphorylation in the hypothalamus in response to insulin, leptin or refeeding was impaired in mice on HFD or in db/db mice. Chronic CLK2 inhibition in the hypothalamus was associated with a slight increase in the fasting blood glucose levels, reduction in PEPCK (phosphoenolpyruvate carboxykinase) expression in the liver and enhanced glucose production from pyruvate, suggesting a regulation of hepatic glucose production. Further, overexpressing CLK2 in the mediobasal hypothalami of mice on HFD or in db/db mice by adenovirus partially reversed the obese phenotype.
Thus, our results suggest that protein CLK2 integrates some important hypothalamic pathways, and may be a promising molecule for new therapeutic approaches for obesity and diabetes.
In light of forensic evidence indicating duplication and/or manipulation of western blot images the Editor-in-Chief is retracting the article cited above.
Aims/hypothesis Diet-induced obesity (DIO) is associated with insulin resistance in liver and muscle, but not in adipose tissue. Mice with fat-specific disruption of the gene encoding the insulin ...receptor are protected against DIO and glucose intolerance. In cell culture, glutamine induces insulin resistance in adipocytes, but has no effect in muscle cells. We investigated whether supplementation of a high-fat diet with glutamine induces insulin resistance in adipose tissue in the rat, improving insulin sensitivity in the whole animal. Materials and methods Male Wistar rats received standard rodent chow or a high-fat diet (HF) or an HF supplemented with alanine or glutamine (HFGln) for 2 months. Light microscopy and morphometry, oxygen consumption, hyperinsulinaemic-euglycaemic clamp and immunoprecipitation/immunoblotting were performed. Results HFGln rats showed reductions in adipose mass and adipocyte size, a decrease in the activity of the insulin-induced IRS-phosphatidylinositol 3-kinase (PI3-K)-protein kinase B-forkhead transcription factor box 01 pathway in adipose tissue, and an increase in adiponectin levels. These results were associated with increases in insulin-stimulated glucose uptake in skeletal muscle and insulin-induced suppression of hepatic glucose output, and were accompanied by an increase in the activity of the insulin-induced IRS-PI3-K-Akt pathway in these tissues. In parallel, there were decreases in TNFα and IL-6 levels and reductions in c-jun N-terminal kinase (JNK), IκB kinase subunit β (IKKβ) and mammalian target of rapamycin (mTOR) activity in the liver, muscle and adipose tissue. There was also an increase in oxygen consumption and a decrease in the respiratory exchange rate in HFGln rats. Conclusions/interpretation Glutamine supplementation induces insulin resistance in adipose tissue, and this is accompanied by an increase in the activity of the hexosamine pathway. It also reduces adipose mass, consequently attenuating insulin resistance and activation of JNK and IKKβ, while improving insulin signalling in liver and muscle.
Human immunodeficiency virus (HIV) remains a public health priority in Latin America. While the burden of HIV is historically concentrated in urban areas and high-risk groups, subnational estimates ...that cover multiple countries and years are missing. This paucity is partially due to incomplete vital registration (VR) systems and statistical challenges related to estimating mortality rates in areas with low numbers of HIV deaths. In this analysis, we address this gap and provide novel estimates of the HIV mortality rate and the number of HIV deaths by age group, sex, and municipality in Brazil, Colombia, Costa Rica, Ecuador, Guatemala, and Mexico.
We performed an ecological study using VR data ranging from 2000 to 2017, dependent on individual country data availability. We modeled HIV mortality using a Bayesian spatially explicit mixed-effects regression model that incorporates prior information on VR completeness. We calibrated our results to the Global Burden of Disease Study 2017.
All countries displayed over a 40-fold difference in HIV mortality between municipalities with the highest and lowest age-standardized HIV mortality rate in the last year of study for men, and over a 20-fold difference for women. Despite decreases in national HIV mortality in all countries-apart from Ecuador-across the period of study, we found broad variation in relative changes in HIV mortality at the municipality level and increasing relative inequality over time in all countries. In all six countries included in this analysis, 50% or more HIV deaths were concentrated in fewer than 10% of municipalities in the latest year of study. In addition, national age patterns reflected shifts in mortality to older age groups-the median age group among decedents ranged from 30 to 45 years of age at the municipality level in Brazil, Colombia, and Mexico in 2017.
Our subnational estimates of HIV mortality revealed significant spatial variation and diverging local trends in HIV mortality over time and by age. This analysis provides a framework for incorporating data and uncertainty from incomplete VR systems and can help guide more geographically precise public health intervention to support HIV-related care and reduce HIV-related deaths.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Loss-of-Function Mutation in Toll-Like Receptor 4 Prevents Diet-Induced Obesity and Insulin Resistance
Daniela M.L. Tsukumo 1 ,
Marco A. Carvalho-Filho 1 ,
José B.C. Carvalheira 1 ,
Patrícia O. Prada ...1 ,
Sandro M. Hirabara 2 ,
André A. Schenka 3 ,
Eliana P. Araújo 1 ,
José Vassallo 3 ,
Rui Curi 2 ,
Lício A. Velloso 1 and
Mario J.A. Saad 1
1 Department of Internal Medicine, State University of Campinas, Campinas, São Paulo, Brazil
2 Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
3 Department of Pathology, State University of Campinas, Campinas, São Paulo, Brazil
Address correspondence and reprint requests to Mario J.A. Saad, MD, Departamento de Clínica Médica, FCM-UNICAMP, Cidade Universitária
Zeferino Vaz, Campinas, SP, Brazil, 13081-970. E-mail: msaad{at}fcm.unicamp.br
Abstract
Obesity is associated with insulin resistance and a state of abnormal inflammatory response. The Toll-like receptor (TLR)4
has an important role in inflammation and immunity, and its expression has been reported in most tissues of the body, including
the insulin-sensitive ones. Because it is activated by lipopolysaccharide and saturated fatty acids, which are inducers of
insulin resistance, TLR4 may be a candidate for participation in the cross-talk between inflammatory and metabolic signals.
Here, we show that C3H/HeJ mice, which have a loss-of-function mutation in TLR4, are protected against the development of
diet-induced obesity. In addition, these mice demonstrate decreased adiposity, increased oxygen consumption, a decreased respiratory
exchange ratio, improved insulin sensitivity, and enhanced insulin-signaling capacity in adipose tissue, muscle, and liver
compared with control mice during high-fat feeding. Moreover, in these tissues, control mice fed a high-fat diet show an increase
in IκB kinase complex and c-Jun NH 2 -terminal kinase activity, which is prevented in C3H/HeJ mice. In isolated muscles from C3H/HeJ mice, protection from saturated
fatty acid–induced insulin resistance is observed. Thus, TLR4 appears to be an important mediator of obesity and insulin resistance
and a potential target for the therapy of these highly prevalent medical conditions.
CLS, crown-like structure
ELISA, enzyme-linked immunosorbent assay
FFA, free fatty acid
HFD, high-fat diet
IGTT, intraperitoneal glucose tolerance test
IκBα, inhibitor of nuclear factor-κB
IKKβ, IκB kinase complex
IL, interleukin
IR, insulin receptor
IRS-1, insulin receptor substrate-1
JNK, c-Jun NH2-terminal kinase
LPS, lipopolysaccharide
NK-κB, nuclear factor-κB
RER, respiratory exchange ratio
TNF, tumor necrosis factor
TLR, Toll-like receptor
WAT, white adipose tissue
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 22 May 2007. DOI: 10.2337/db06-1595.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted May 18, 2007.
Received November 14, 2006.
DIABETES
Aims/hypothesisDiet-induced obesity (DIO) is associated with insulin resistance in liver and muscle, but not in adipose tissue. Mice with fat-specific disruption of the gene encoding the insulin ...receptor are protected against DIO and glucose intolerance. In cell culture, glutamine induces insulin resistance in adipocytes, but has no effect in muscle cells. We investigated whether supplementation of a high-fat diet with glutamine induces insulin resistance in adipose tissue in the rat, improving insulin sensitivity in the whole animal.Materials and methodsMale Wistar rats received standard rodent chow or a high-fat diet (HF) or an HF supplemented with alanine or glutamine (HFGln) for 2 months. Light microscopy and morphometry, oxygen consumption, hyperinsulinaemic–euglycaemic clamp and immunoprecipitation/immunoblotting were performed.ResultsHFGln rats showed reductions in adipose mass and adipocyte size, a decrease in the activity of the insulin-induced IRS–phosphatidylinositol 3-kinase (PI3-K)–protein kinase B–forkhead transcription factor box 01 pathway in adipose tissue, and an increase in adiponectin levels. These results were associated with increases in insulin-stimulated glucose uptake in skeletal muscle and insulin-induced suppression of hepatic glucose output, and were accompanied by an increase in the activity of the insulin-induced IRS–PI3-K–Akt pathway in these tissues. In parallel, there were decreases in TNFα and IL-6 levels and reductions in c-jun N-terminal kinase (JNK), IκB kinase subunit β (IKKβ) and mammalian target of rapamycin (mTOR) activity in the liver, muscle and adipose tissue. There was also an increase in oxygen consumption and a decrease in the respiratory exchange rate in HFGln rats.Conclusions/interpretationGlutamine supplementation induces insulin resistance in adipose tissue, and this is accompanied by an increase in the activity of the hexosamine pathway. It also reduces adipose mass, consequently attenuating insulin resistance and activation of JNK and IKKβ, while improving insulin signalling in liver and muscle.
To get some additional insight on the mechanisms of the effect of salt intake on body weight.
Rats were fed a low (LSD), normal (NSD), or high (HSD) salt diet. In a first set, body weight, tail-cuff ...blood pressure, fasting plasma thyroid-stimulating hormone, triiodothyronine,
l-thyroxine, glucose, insulin, and angiotensin II were measured. Angiotensin II content was determined in white and brown adipose tissues. Uncoupling protein 1 expression was measured in brown adipose tissue. In a second set, body weight, food intake, energy balance, and plasma leptin were determined. In a third set of rats, motor activity and body weight were evaluated.
Blood pressure increased on HSD. Body weight was similar among groups at weaning, but during adulthood it was lower on HSD and higher on LSD. Food intake,
l-thyroxine concentration, uncoupling protein 1 expression and energy expenditure were higher in HSD rats, while non-fasting leptin concentration was lower in these groups compared to NSD and LSD animals. Plasma thyroid-stimulating hormone decreased on both HSD and LSD while plasma glucose and insulin were elevated only on LSD. A decrease in plasma angiotensin II was observed in HSD rats. On LSD, an increase in brown adipose tissue angiotensin II content was associated to decreased uncoupling protein 1 expression and energy expenditure. In this group, a low angiotensin II content in white adipose tissue was also found. Motor activity was not influenced by the dietary salt content.
Chronic alteration in salt intake is associated with changes in body weight, food intake, hormonal profile, and energy expenditure and tissue angiotensin II content.
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