Increased Energy Expenditure, Dietary Fat Wasting, and Resistance to Diet-Induced Obesity in Mice Lacking Renin

Takahashi, Nobuyuki; Li, Feng; Hua, Kunjie; Deng, Jianbei; Wang, Chih Hong; Bowers, Robert R.; Bartness, Timothy J.; Kim, Hyung Suk; Harp, Joyce B.

doi:10.1016/j.cmet.2007.10.011

Cited by 105 publications

(139 citation statements)

References 33 publications

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“…Serum leptin levels were analyzed by Elisa using a kit from RayBiotech (Norcross, GA). Steatocrit was analyzed using the perchloric acid method as described (51).…”

Section: Methodsmentioning

confidence: 99%

Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

Kang¹,

Okamoto²,

Takeda³

et al. 2011

Physiological Genomics

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AM. Transcriptional profiling reveals a role for ROR␣ in regulating gene expression in obesity-associated inflammation and hepatic steatosis. Physiol Genomics 43: 818 -828, 2011. First published May 3, 2011 doi:10.1152/physiolgenomics.00206.2010.-Retinoid-related orphan receptor (ROR)␣4 is the major ROR␣ isoform expressed in adipose tissues and liver. In this study we demonstrate that ROR␣-deficient staggerer mice (ROR␣ sg/sg ) fed with a high-fat diet (HFD) exhibited reduced adiposity and hepatic triglyceride levels compared with wild-type (WT) littermates and were resistant to the development of hepatic steatosis, adipose-associated inflammation, and insulin resistance. Gene expression profiling showed that many genes involved in triglyceride synthesis and storage, including Cidec, Cidea, and Mogat1, were expressed at much lower levels in liver of ROR␣ sg/sg mice. In contrast, overexpression of ROR␣ in mouse hepatoma Hepa1-6 cells significantly increased the expression of genes that were repressed in ROR␣ sg/sg liver, including Sult1b1, Adfp, Cidea, and ApoA4. ChIP and promoter analysis suggested that several of these genes were regulated directly by ROR␣. In addition to reduced lipid accumulation, inflammation was greatly diminished in white adipose tissue (WAT) of ROR␣ sg/sg mice fed with an HFD. The infiltration of macrophages and the expression of many immune response and proinflammatory genes, including those encoding various chemo/cytokines, Toll-like receptors, and TNF signaling proteins, were significantly reduced in ROR␣ sg/sg WAT. Moreover, ROR␣ sg/sg mice fed with an HFD were protected from the development of insulin resistance. ROR␣ sg/sg mice consumed more oxygen and produced more carbon dioxide, suggesting increased energy expenditure in this genotype. Our study indicates that ROR␣ plays a critical role in the regulation of several aspects of metabolic syndrome. Therefore, ROR␣ may provide a novel therapeutic target in the management of obesity and associated metabolic diseases. staggerer mice; obesity; metabolic syndrome; macrophage; insulinresistance; diabetes; retinoid-related orphan receptors OBESITY IS A MAJOR GLOBAL health concern. In the United States alone, 30% of the general population is obese and an estimated 66% of all adults are overweight (40). Obesity is associated with an elevated risk of several pathologies, including Type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease (NAFLD), cancer, and airway disease (18,36). The molecular links between obesity and these diseases are beginning to be understood. It is now well recognized that obesity is associated with chronic low-grade inflammation and that inflammatory processes play an important role in obesity and related pathologies (18,44,53). Infiltration of macrophages and various T-lymphocytes in hypertrophic adipose tissues have been considered as important early events in the development of obesity-associated complications (14, 38, 57) and the release of proinflammatory cytokines by adipose tissue plays a key ...

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“…Serum leptin levels were analyzed by Elisa using a kit from RayBiotech (Norcross, GA). Steatocrit was analyzed using the perchloric acid method as described (51).…”

Section: Methodsmentioning

confidence: 99%

Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

Kang¹,

Okamoto²,

Takeda³

et al. 2011

Physiological Genomics

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“…Genetic disruption of several RAS components in rodent models results in a protection from high-fat diet (HFD)-induced obesity. [15][16][17] In fact, knockout of renin, 16 ACE, 17 and liver-specific deletion of Ang II receptor type 1 18 also reduces hepatic steatosis in rodent models. The role of Ang-(1-7) in metabolic regulation has been recently described.…”

mentioning

confidence: 99%

“…Genetic disruption of several RAS components in rodent models results in a protection from high-fat diet (HFD)-induced obesity. [15][16][17] In fact, knockout of renin, …”

mentioning

confidence: 99%

Oral Formulation of Angiotensin-(1–7) Improves Lipid Metabolism and Prevents High-Fat Diet–Induced Hepatic Steatosis and Inflammation in Mice

et al. 2013

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Abstract-Angiotensin (Ang)-(1-7) has been described as an important tool on treating and preventing metabolic disorders. In this study, we aimed to evaluate the effect of an oral formulation of Ang-(1-7) included in hydroxypropylβ-cyclodextrin (HPβCD/Ang- [1][2][3][4][5][6][7]) on hepatic function, steatosis, and on liver inflammatory markers expression in mice treated with a high-fat diet. Male FVB/N mice were divided into 4 groups and fed for 60 days, with each group receiving 1 of the following diets: standard diet+HPβCD, standard diet+Ang-(1-7)/HPβCD, high-fat diet+HPβCD, or highfat diet+Ang-[1-7]/HPβCD. Body weight, food intake, and blood parameters, such as total cholesterol, triglyceride, alaninetransaminases, and aspartate transaminases, were evaluated. Immunohistochemical analyses were performed for inflammatory markers tumor necrosis factor-α and interleukin-6. Expression of angiotensin converting enzyme, angiotensin-converting enzyme-2, interleukin-1β, tumor necrosis factor-α, interleukin-6, transforming growth factor-β, acetyl-CoA carboxylase, carbohydrate-responsive element-binding protein, peroxisome proliferator-activated receptor-γ, and sterol regulatory element-binding proteins-1c was evaluated by quantitative real-time polymerase chain reaction. The major findings of our study included reduced liver fat mass and weight, decreased plasma total cholesterol, triglyceride, and alaninetransaminase enzyme levels in the oral Ang-(1-7)-treated groups compared with the control groups. These results were accompanied by a significant reduction in tumor necrosis factor-α and interleukin-6 mRNA expression in the liver. Analyses of liver adipogenesis-related genes by quantitative real-time polymerase chain reaction showed that acetyl-CoA carboxylase, peroxisome proliferator-activated receptor-γ, and sterol regulatory element-binding proteins1c mRNA expression were significantly suppressed. In conclusion, we observed that treatment with Ang-(1-7) improved metabolism and decreased proinflammatory profile and fat deposition in liver of mice. The renin-angiotensin system (RAS) is now recognized to play an important role in the development of cardiovascular and metabolic disorders. [10][11][12][13] The RAS consists primarily of an enzymatic cascade in which angiotensinogen is converted to angiotensin (Ang) I and subsequently to Ang II by the actions of renin and Ang-converting enzyme (ACE), respectively. 14 Ang-(1-7) is formed mainly from Ang II by ACE-2 and indirectly from Ang I.14 The ACE-2/Ang-(1-7)/Mas axis has been suggested as an important counter-regulatory arm in the RAS with effects opposing those of ACE/Ang II/Ang II receptor, type 1. 13Recent studies showed an important participation of RAS in the nonalcoholic fatty liver disease (NAFLD) development and progression. The Ang II has been implicated as a major player in the altered hepatic lipid metabolism observed in NAFLD. Genetic disruption of several RAS components in rodent models results in a protection from high-fat diet (HFD)-induced obesity. [15...

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“…Mice lacking renin exhibit lower blood pressure and undetectable plasma levels of renin, Ang I and Ang II (412) . Unexpectedly, these mice are resistant to dietinduced obesity via an increased metabolic rate and partly through a gastrointestinal loss of dietary fat, but not from increased locomotor activity or reduced food intake (14) . Some, but not all, of the observed alterations were reversed after Ang II administration.…”

Section: Reninmentioning

confidence: 99%

“…Better known is the involvement of ghrelin, cholecystokinin (CCK), glucagon-like peptide (GLP)-1 and peptide YY (PYY) 3 -36 , produced by the gut, in energy homeostasis (19) . Even the kidney, through the production of renin, appears to regulate body weight, because mice lacking this hormone exhibit resistance to diet-induced obesity (14) . In addition, the skeleton has recently emerged as an endocrine organ, with effects on body weight control and glucose homeostasis through the actions of bone-derived factors such as osteocalcin and osteopontin (15) .…”

Section: Introductionmentioning

confidence: 99%

Peripheral signalling involved in energy homeostasis control

2012

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The alarming prevalence of obesity has led to a better understanding of the molecular mechanisms controlling energy homeostasis. Regulation of energy intake and expenditure is more complex than previously thought, being influenced by signals from many peripheral tissues. In this sense, a wide variety of peripheral signals derived from different organs contributes to the regulation of body weight and energy expenditure. Besides the well-known role of insulin and adipokines, such as leptin and adiponectin, in the regulation of energy homeostasis, signals from other tissues not previously thought to play a role in body weight regulation have emerged in recent years. The role of fibroblast growth factor 21 (FGF21), insulin-like growth factor 1 (IGF-I), and sex hormone-binding globulin (SHBG) produced by the liver in the regulation of body weight and insulin sensitivity has been recently described. Moreover, molecules expressed by skeletal muscle such as myostatin have also been involved in adipose tissue regulation. Better known is the involvement of ghrelin, cholecystokinin, glucagon-like peptide 1 (GLP-1) and PYY 3 -36 , produced by the gut, in energy homeostasis. Even the kidney, through the production of renin, appears to regulate body weight, with mice lacking this hormone exhibiting resistance to diet-induced obesity. In addition, the skeleton has recently emerged as an endocrine organ, with effects on body weight control and glucose homeostasis through the actions of bone-derived factors such as osteocalcin and osteopontin. The comprehension of these signals will help in a better understanding of the aetiopathology of obesity, contributing to the potential development of new therapeutic targets aimed at tackling excess body fat accumulation.

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Increased Energy Expenditure, Dietary Fat Wasting, and Resistance to Diet-Induced Obesity in Mice Lacking Renin

Cited by 105 publications

References 33 publications

Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

Oral Formulation of Angiotensin-(1–7) Improves Lipid Metabolism and Prevents High-Fat Diet–Induced Hepatic Steatosis and Inflammation in Mice

Peripheral signalling involved in energy homeostasis control

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