Peroxisome Proliferator-Activated Receptors-Alpha and Gamma Are Targets to Treat Offspring from Maternal Diet-Induced Obesity in Mice

Magliano, D’Angelo Carlo; Bargut, Thereza Cristina Lonzetti; Carvalho, Simone; Águila, Márcia Barbosa; Mandarim-de-Lacerda, Carlos Alberto; Souza-Mello, Vanessa

doi:10.1371/journal.pone.0064258

Cited by 81 publications

(63 citation statements)

References 55 publications

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“…PPAR-alpha gene and protein expression were reduced in the liver of offspring of HF dams parallel to increased gene and protein expression of PPAR-gamma. As a result, the hepatic expression of the PPAR-alpha target gene CPT-1 was decreased, because the expression of the PPAR gamma target genes SREBP-1c was elevated [31] . This pattern of gene and protein expression explains the early NAFLD onset in the offspring of obese dams [32] , albeit with a discrete overweight.…”

Section: Models Nafldmentioning

confidence: 99%

“…Additionally, hepatic insulin resistance was detected in obese dams offspring through enhanced hepatic expression of glucose 6 phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) [31] . Both enzymes are crucial to hepatic gluconeogenesis and are activated by glucagon during the fasting period and inhibited by insulin at the postprandial stage.…”

Section: Models Nafldmentioning

confidence: 99%

“…In resemblance with telmisartan, ragaglitazar, a dual PPAR-alpha/PPAR-gamma agonist, tackled hepatic insulin resistance, hepatic steatosis and overweight in a mouse model of metabolic syndrome, whereas total PPAR-gamma agonist rosiglitazone elicited visceral adiposity and hepatomegaly [68] . PanPPAR activation by bezafibrate triggered beneficial effects in offspring from obese dams derived from PPARalpha activation (increased CPT-1 expression in the liver); PPAR-beta/delta activation (reduced gluconeogenesis due to low hepatic G6Pase and PEPCK expression caused by downregulation of FOXO-1 gene); and PPAR-gamma activation (high FAT/CD36 liver expression, causing greater hepatic lipid oxidation in conjunction with the high CPT-1 expression) [31] . Bezafibrate and GW501516, a PPAR-delta agonist, inhibited NASH development in mice fed a methionine choline-deficient diet.…”

Section: Targeting Ppars To Treat Nafldmentioning

confidence: 99%

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Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease

Souza-Mello¹

2015

WJH

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152

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and microsomal omega-oxidation, being markedly decreased by high-fat (HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR-beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs. AbstractLately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease (NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation (mitochondrial and peroxisomal)

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Section: Models Nafldmentioning

confidence: 99%

Section: Models Nafldmentioning

confidence: 99%

Section: Targeting Ppars To Treat Nafldmentioning

confidence: 99%

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Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease

Souza-Mello¹

2015

WJH

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152

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“…Moreover, the transcription factor NFκB mediates inflammation in obesity, which can be suppressed by n-3 PUFAs, leading to improvement of IR (Siriwardhana et al, 2012). The effects of n-3 PUFAs in WAT are also mediated by PPARγ, whose activation enhances adiponectin production and promotes the apoptosis of large adipocytes, increasing the number of small adipocytes, which are more insulin sensitive (Magliano et al, 2013). Fig.…”

Section: Polyunsaturated Fas (Pufas)mentioning

confidence: 99%

Animal Models of Nutritional Induction of Type 2 Diabetes Mellitus

Barbosa-da-Silva¹,

Sarmento²,

Bargut³

et al. 2014

Int. J. Morphol.

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SUMMARY:Type 2 diabetes mellitus (DM2) is the most common chronic metabolic disease, affecting approximately 6% of the adult population in the Western world. This condition is a major cause of cardiovascular disease, blindness, renal failure, and amputations, with increasing prevalence worldwide. The influence of obesity on type 2 diabetes risk is determined by the degree of obesity and by body fat localization, with insulin resistance (IR) being the main link between these metabolic diseases. Experimental studies have shown that dietary factors, and particularly lipids, are strongly positively associated with body mass (BM) gain; IR; and, consequently, type 2 diabetes. Similarly, excessive consumption of energy-dense carbohydrate-rich foods can trigger the onset of type 2 diabetes. Additionally, maternal dietary inadequacies at conception and/or during the gestational period have been proposed to lead to developmental programming of excessive BM gain and metabolic disturbances in offspring, such as abnormal glucose homeostasis, reduced wholebody insulin sensitivity, impaired beta-cell insulin secretion and changes in the structure of the pancreas. Metabolic disruption is strongly associated with deleterious effects on beta-cell development and function. However, alterations in the amount and quality of dietary fat can modify glucose metabolism and insulin sensitivity. In this way, certain oils have gained attention in experimental research for their beneficial effects. Olive oil, a source of monounsaturated fatty acids (MUFAs), got attention in the past for its capacity to prevent cardiovascular diseases. Nevertheless, it is currently known that this oil also improves insulin sensitivity and glycemic control. Canola oil, flaxseed oil and especially fish oil (rich in n-3 polyunsaturated fatty acids) were first described as effective dietary nutrients against hypertriglyceridemia but now are known to have positive effects on glucose metabolism as well.

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“…Peroxisome proliferator-activated receptors (PPARs) are transcription factors responsible for the transcription of genes involved in hepatic beta-oxidation and lipogenesis (Wahli & Michalik, 2012). HF-fed mothers cause disrupted PPAR balance in the first generation offspring, favoring the high expression of PPAR-gamma (lipogenic factor) concomitant to decreased expression of PPAR-alpha, essential to mitochondrial betaoxidation (Magliano et al, 2013). Hepatic impairments have been described in both newborn mice (Bringhenti et al, 2015) and in adult mice (Alfaradhi et al).…”

Section: Introductionmentioning

confidence: 99%

Both Hepatic Lipogenesis and Beta-Oxidation are Altered in Offspring of Mothers Fed a High-Fat Diet in the First Two Generations (F1 and F2)

et al. 2015

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SUMMARY:The high fat (HF) fed mothers may program susceptibility in offspring to chronic diseases and affect subsequent generations. The present study evaluated the liver structure in adulthood, focusing on the F1 and F2 generations. Females C57BL/6 (F0) were fed standard chow (SC) or HF diet (8 weeks) prior to mating and during the gestation and lactation to provide the F1 generation (SC-F1 and HF-F1). All other mothers and offspring fed SC. At 3 months old, F1 females were mated to produce the F2 generation (SC-F2 and HF-F2). The liver was kept in several fragments and prepared for histological analysis or frozen for biochemical and molecular analyzes. The F1 and F2 offspring were studied at 3 months old. HF-F1 had higher body mass (BM) compared to SC-F1 (P= 0.001), but not HF-F2 compared to SC-F2. HF-F1 had glucose intolerance when compared to SC-F1, but not HF-F2 compared to SC-F2. HF-F1 (P= 0.009) and HF-F2 (P= 0.03) showed hyperinsulinemia compared to their counterparts. Both groups HF-F1 and HF-F2 showed more steatosis than the SC counterparts (F1 and F2, P<0.0001). HF-F1 showed increased expression of PPAR-gamma and SREBP1-c compared to SC-F1 (P= 0.01). HF-F2 showed increased PPAR-gamma expression compared to SC-F2 (P= 0.04). In conclusion, HF-fed mother impairs both lipogenesis and beta-oxidation pathways in F1 through upregulation of PPAR-gamma and downregulation of PPAR-alpha. In F2, the only lipogenesis is enhanced, but it causes a disrupted PPAR balance, favoring the hepatic lipid accumulation and impaired metabolism in these animals that were not directly exposed to the maternal HF intake.

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Peroxisome Proliferator-Activated Receptors-Alpha and Gamma Are Targets to Treat Offspring from Maternal Diet-Induced Obesity in Mice

Cited by 81 publications

References 55 publications

Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease

Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease

Animal Models of Nutritional Induction of Type 2 Diabetes Mellitus

Both Hepatic Lipogenesis and Beta-Oxidation are Altered in Offspring of Mothers Fed a High-Fat Diet in the First Two Generations (F1 and F2)

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