This is a publicly available preprint of a publication that itself is not publicly available (without charge). There are some typos, and I can't say what differs from the final version, but it's probably close to the same. This is a report of research in MICE, but it is an interesting avenue of investigation, especially for those of us who have issues with wheat products:
www.scribd.com/doc/120209305/Gluten-Free-Diet-Reduces-Adiposity-Inflammation-and-Insulin-Resistance-Associated-With-the-Induction-of-PPAR-Alpha
Final Abstract and publication information:
J Nutr Biochem. 2012 Dec 17. pii: S0955-2863(12)00226-4. doi: 10.1016/j.jnutbio.2012.08.009. [Epub ahead of print]
Gluten-free diet reduces adiposity, inflammation and insulin resistance associated with the induction of PPAR-alpha and PPAR-gamma expression.
Soares FL, de Oliveira Matoso R, Teixeira LG, Menezes Z, Pereira SS, Alves AC, Batista NV, de Faria AM, Cara DC, Ferreira AV, Alvarez-Leite JI.
Departamento de Alimentos, Faculdade de Farmácia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil; Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. Electronic address: [email protected].
AbstractGluten exclusion (protein complex present in many cereals) has been proposed as an option for the prevention of diseases other than coeliac disease. However, the effects of gluten-free diets on obesity and its mechanisms of action have not been studied. Thus, our objective was to assess whether gluten exclusion can prevent adipose tissue expansion and its consequences. C57BL/6 mice were fed a high-fat diet containing 4.5% gluten (Control) or no gluten (GF). Body weight and adiposity gains, leukocyte rolling and adhesion, macrophage infiltration and cytokine production in adipose tissue were assessed. Blood lipid profiles, glycaemia, insulin resistance and adipokines were measured. Expression of the PPAR-α and γ, lipoprotein lipase (LPL), hormone sensitive lipase (HSL), carnitine palmitoyl acyltransferase-1 (CPT-1), insulin receptor, GLUT-4 and adipokines were assessed in epidydimal fat. Gluten-free animals showed a reduction in body weight gain and adiposity, without changes in food intake or lipid excretion. These results were associated with up-regulation of PPAR-α, LPL, HSL and CPT-1, which are related to lipolysis and fatty acid oxidation. There was an improvement in glucose homeostasis and pro-inflammatory profile-related overexpression of PPAR-γ. Moreover, intravital microscopy showed a lower number of adhered cells in the adipose tissue microvasculature. The overexpression of PPAR-γ is related to the increase of adiponectin and GLUT-4. Our data support the beneficial effects of gluten-free diets in reducing adiposity gain, inflammation and insulin resistance. The data suggests that diet gluten exclusion should be tested as a new dietary approach to prevent the development of obesity and metabolic disorders.
From the preprint Discussion section:
Some indirect evidence suggests that gluten exclusion provides benefits not only to coeliac patients, but also to those suffering from certain chronic diseases, such as obesity[2–6]. However, to our knowledge, this is the first study investigating the effects and impact of a gluten-free diet on obesity and lipid and glucose metabolism.
The gluten-free diet slowed body weight gain, thereby reducing visceral adiposity and adipocyte size. Because adipocyte hypertrophy is one of the major factors responsible for adipose tissue inflammation and glucose homeostasis imbalance, dietary approaches that restrict adipocyte expansion are also likely to improve insulin resistance[9,20].
Since our results did not reveal any differences in food intake (P=.533), fecal lipid excretion (P=.904) or lipid content in blood, muscle and liver, we believe that the differences found between groups on fat content in adipose tissue are the consequence of metabolic alterations in lipid and glucose metabolism in GF group instead reduction of lipid absorption.
Therefore, the lower adiposity in the GF animals occurred despite the unchanged food intake, faeces lipid excretion and lipogenesis in adipose tissue. Reduced adiposity in mice fed GF diet seem to be mediated, at least in part, by the increased expression of the lipolytic enzyme and mitochondrial oxidative, such as HSL and CPT-1, as well as increased expression of PPAR-α and γ, well known transcription factors involved in the adipose tissue remodelling.
PPARs play an important role in lipid and glucose homeostasis. PPAR-α agonists are related to increased fat oxidation and the improvement of insulin sensitivity[21]. PPAR-α agonists also decrease intracellular fatty acyl CoA and malonyl CoA and increase fatty acid oxidation[22,23]. The latter is favoured by the induction of CPT-1 expression by PPAR-α, which permits the influx of fatty acids into mitochondria[24]. Our results suggest that a gluten-free diet could inhibit the accumulation of triacylglycerol in adipose tissue by inducing concomitantly lipolysis of intracellular triglycerides (increased expression of HSL) and increasing mitochondrial oxidation of the fatty acids (released after HSL action) as suggested by the increased expression of CPT-1. Corroborating those results are the lower lipid accumulation in epididymal fat of GF mice and the similar lipid concentration in blood and liver.
Our results also showed the protective effects of a gluten-free diet on glucose homeostasis. Glycaemia, insulinaemia, HOMA-IR and insulin sensitivity were all improved in the GF mice. These effects may be related to the lower accumulation of visceral adiposity[9–12] in the GF mice, among other factors. Gluten exclusion has been also related to a reduction in the incidence of type 1 diabetes mellitus[3–5].
Our results are supported by a previous study showing that pigs fed a cereal-free diet had improved insulin sensitivity associated with lower concentrations of C-reactive protein[6].
We also showed that animals fed a gluten-free diet have lower leukocyte adhesion, macrophage infiltration and pro-inflammatory cytokine production, e.g., MCP-1/CCL-2, TNF-α and IL-6. These results are consistent with a gliadin-macrophage interaction, which triggers an inflammatory response, inducing the expression and production of pro-inflammatory cytokines[25].
Several studies have highlighted the relationship between excess adiposity, inflammation and insulin resistance[11,26–28]. Macrophage infiltration is correlated with an increase in adiposity[27], especially at the visceral site[28]. The expansion of visceral adipose tissue releases chemokines involved in macrophage recruitment[11,29]. Both activated macrophages and hypertrophic adipocytes are able to produce large amount adipokines, which act negatively oninsulin signalling[9]. Our results confirm the macrophage-adipocyte connection because the exclusion of gluten reduced adipocyte size,leukocyte adhesion and macrophage infiltration in adipose tissue,resulting in lower concentrations of pro-inflammatory cytokines and adipokines, including TNF-α, IL-6, leptin and resistin, which areknown to induce IR [7,29–34].
In addition to adiposity, the gluten-free diet played an important role in reducing insulin resistance by increasing the expression of PPAR-γ, insulin receptor, GLUT-4 and adiponectin[33–35]. PPAR-γ is abundantly expressed in adipose tissue, and it is the target of anti-diabetic drugs, such as the glitazones. PPAR-γ agonists improve insulin sensitivity and glucose metabolism, reduce inflammation and promote the differentiation of pre-adipocytes into adipocytes[24,36], resulting in smaller and more insulin-sensitive adipocytes[31].
It is known that PPAR-γ stimulates GLUT-4 and adiponectin gene expression in adipose tissue[33,37]. In contrast, TNF-α is related to the down-regulation and degradation of PPAR-γ[29]. Therefore, our data suggest that the reduction of TNF-α production after gluten exclusion leads to increased PPAR-γ levels, triggering the higher expression of adiponectin and GLUT-4, which contributes to the improvement in insulin sensitivity in the GF group.
It has been previously demonstrated that gluten products may accumulate in the lysosomes of intestinal cells, leading to metabolic reactions that culminate in the proteosomal degradation of PPAR-γ [38]. This may represent another mechanism by which gluten exclusion attenuates inflammation and glucose homeostasis.
Taken together, our data suggest that the improvement in glucose homeostasis noted with the gluten-free diet primarily involves a reduction of the inflammatory profile, leading to an increase in the transcription of PPAR-γ and the metabolic modulation linked to PPAR-γ viability.
In conclusion, our data show that the removal of wheat gluten from the diet exerts a protective effect against body weight and adiposity gains through, at least in part, by provoke lipid mobilization and oxidation in adipose tissue, causing a lower accumulation of lipid. In addition, a gluten-free diet improves insulin sensitivity through the suppression of the inflammatory profile, leading to an increase in PPAR-γ expression that culminates in systemic increased of adiponectin levels and adipose GLUT-4 expression concomitant withr educed resistin concentrations. Our data support the beneficial effects of gluten exclusion in reducing body weight and adiposity gain, inflammation and insulin resistance.
www.scribd.com/doc/120209305/Gluten-Free-Diet-Reduces-Adiposity-Inflammation-and-Insulin-Resistance-Associated-With-the-Induction-of-PPAR-Alpha
Final Abstract and publication information:
J Nutr Biochem. 2012 Dec 17. pii: S0955-2863(12)00226-4. doi: 10.1016/j.jnutbio.2012.08.009. [Epub ahead of print]
Gluten-free diet reduces adiposity, inflammation and insulin resistance associated with the induction of PPAR-alpha and PPAR-gamma expression.
Soares FL, de Oliveira Matoso R, Teixeira LG, Menezes Z, Pereira SS, Alves AC, Batista NV, de Faria AM, Cara DC, Ferreira AV, Alvarez-Leite JI.
Departamento de Alimentos, Faculdade de Farmácia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil; Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. Electronic address: [email protected].
AbstractGluten exclusion (protein complex present in many cereals) has been proposed as an option for the prevention of diseases other than coeliac disease. However, the effects of gluten-free diets on obesity and its mechanisms of action have not been studied. Thus, our objective was to assess whether gluten exclusion can prevent adipose tissue expansion and its consequences. C57BL/6 mice were fed a high-fat diet containing 4.5% gluten (Control) or no gluten (GF). Body weight and adiposity gains, leukocyte rolling and adhesion, macrophage infiltration and cytokine production in adipose tissue were assessed. Blood lipid profiles, glycaemia, insulin resistance and adipokines were measured. Expression of the PPAR-α and γ, lipoprotein lipase (LPL), hormone sensitive lipase (HSL), carnitine palmitoyl acyltransferase-1 (CPT-1), insulin receptor, GLUT-4 and adipokines were assessed in epidydimal fat. Gluten-free animals showed a reduction in body weight gain and adiposity, without changes in food intake or lipid excretion. These results were associated with up-regulation of PPAR-α, LPL, HSL and CPT-1, which are related to lipolysis and fatty acid oxidation. There was an improvement in glucose homeostasis and pro-inflammatory profile-related overexpression of PPAR-γ. Moreover, intravital microscopy showed a lower number of adhered cells in the adipose tissue microvasculature. The overexpression of PPAR-γ is related to the increase of adiponectin and GLUT-4. Our data support the beneficial effects of gluten-free diets in reducing adiposity gain, inflammation and insulin resistance. The data suggests that diet gluten exclusion should be tested as a new dietary approach to prevent the development of obesity and metabolic disorders.
From the preprint Discussion section:
Some indirect evidence suggests that gluten exclusion provides benefits not only to coeliac patients, but also to those suffering from certain chronic diseases, such as obesity[2–6]. However, to our knowledge, this is the first study investigating the effects and impact of a gluten-free diet on obesity and lipid and glucose metabolism.
The gluten-free diet slowed body weight gain, thereby reducing visceral adiposity and adipocyte size. Because adipocyte hypertrophy is one of the major factors responsible for adipose tissue inflammation and glucose homeostasis imbalance, dietary approaches that restrict adipocyte expansion are also likely to improve insulin resistance[9,20].
Since our results did not reveal any differences in food intake (P=.533), fecal lipid excretion (P=.904) or lipid content in blood, muscle and liver, we believe that the differences found between groups on fat content in adipose tissue are the consequence of metabolic alterations in lipid and glucose metabolism in GF group instead reduction of lipid absorption.
Therefore, the lower adiposity in the GF animals occurred despite the unchanged food intake, faeces lipid excretion and lipogenesis in adipose tissue. Reduced adiposity in mice fed GF diet seem to be mediated, at least in part, by the increased expression of the lipolytic enzyme and mitochondrial oxidative, such as HSL and CPT-1, as well as increased expression of PPAR-α and γ, well known transcription factors involved in the adipose tissue remodelling.
PPARs play an important role in lipid and glucose homeostasis. PPAR-α agonists are related to increased fat oxidation and the improvement of insulin sensitivity[21]. PPAR-α agonists also decrease intracellular fatty acyl CoA and malonyl CoA and increase fatty acid oxidation[22,23]. The latter is favoured by the induction of CPT-1 expression by PPAR-α, which permits the influx of fatty acids into mitochondria[24]. Our results suggest that a gluten-free diet could inhibit the accumulation of triacylglycerol in adipose tissue by inducing concomitantly lipolysis of intracellular triglycerides (increased expression of HSL) and increasing mitochondrial oxidation of the fatty acids (released after HSL action) as suggested by the increased expression of CPT-1. Corroborating those results are the lower lipid accumulation in epididymal fat of GF mice and the similar lipid concentration in blood and liver.
Our results also showed the protective effects of a gluten-free diet on glucose homeostasis. Glycaemia, insulinaemia, HOMA-IR and insulin sensitivity were all improved in the GF mice. These effects may be related to the lower accumulation of visceral adiposity[9–12] in the GF mice, among other factors. Gluten exclusion has been also related to a reduction in the incidence of type 1 diabetes mellitus[3–5].
Our results are supported by a previous study showing that pigs fed a cereal-free diet had improved insulin sensitivity associated with lower concentrations of C-reactive protein[6].
We also showed that animals fed a gluten-free diet have lower leukocyte adhesion, macrophage infiltration and pro-inflammatory cytokine production, e.g., MCP-1/CCL-2, TNF-α and IL-6. These results are consistent with a gliadin-macrophage interaction, which triggers an inflammatory response, inducing the expression and production of pro-inflammatory cytokines[25].
Several studies have highlighted the relationship between excess adiposity, inflammation and insulin resistance[11,26–28]. Macrophage infiltration is correlated with an increase in adiposity[27], especially at the visceral site[28]. The expansion of visceral adipose tissue releases chemokines involved in macrophage recruitment[11,29]. Both activated macrophages and hypertrophic adipocytes are able to produce large amount adipokines, which act negatively oninsulin signalling[9]. Our results confirm the macrophage-adipocyte connection because the exclusion of gluten reduced adipocyte size,leukocyte adhesion and macrophage infiltration in adipose tissue,resulting in lower concentrations of pro-inflammatory cytokines and adipokines, including TNF-α, IL-6, leptin and resistin, which areknown to induce IR [7,29–34].
In addition to adiposity, the gluten-free diet played an important role in reducing insulin resistance by increasing the expression of PPAR-γ, insulin receptor, GLUT-4 and adiponectin[33–35]. PPAR-γ is abundantly expressed in adipose tissue, and it is the target of anti-diabetic drugs, such as the glitazones. PPAR-γ agonists improve insulin sensitivity and glucose metabolism, reduce inflammation and promote the differentiation of pre-adipocytes into adipocytes[24,36], resulting in smaller and more insulin-sensitive adipocytes[31].
It is known that PPAR-γ stimulates GLUT-4 and adiponectin gene expression in adipose tissue[33,37]. In contrast, TNF-α is related to the down-regulation and degradation of PPAR-γ[29]. Therefore, our data suggest that the reduction of TNF-α production after gluten exclusion leads to increased PPAR-γ levels, triggering the higher expression of adiponectin and GLUT-4, which contributes to the improvement in insulin sensitivity in the GF group.
It has been previously demonstrated that gluten products may accumulate in the lysosomes of intestinal cells, leading to metabolic reactions that culminate in the proteosomal degradation of PPAR-γ [38]. This may represent another mechanism by which gluten exclusion attenuates inflammation and glucose homeostasis.
Taken together, our data suggest that the improvement in glucose homeostasis noted with the gluten-free diet primarily involves a reduction of the inflammatory profile, leading to an increase in the transcription of PPAR-γ and the metabolic modulation linked to PPAR-γ viability.
In conclusion, our data show that the removal of wheat gluten from the diet exerts a protective effect against body weight and adiposity gains through, at least in part, by provoke lipid mobilization and oxidation in adipose tissue, causing a lower accumulation of lipid. In addition, a gluten-free diet improves insulin sensitivity through the suppression of the inflammatory profile, leading to an increase in PPAR-γ expression that culminates in systemic increased of adiponectin levels and adipose GLUT-4 expression concomitant withr educed resistin concentrations. Our data support the beneficial effects of gluten exclusion in reducing body weight and adiposity gain, inflammation and insulin resistance.
