The Potential of Resveratrol to Act as a Caloric Restriction Mimetic Appears to Be Limited: Insights from Studies in Mice

ABSTRACT Caloric restriction (CR) has been shown repeatedly to prolong the lifespan in laboratory animals, with its benefits dependent on molecular targets forming part of the nutrient signaling network, including the NAD-dependent deacetylase silent mating type information regulation 2 homologue 1 (SIRT1). It has been hypothesized that the stilbene resveratrol (RSV) may counteract age- and obesity-related diseases similarly to CR. In yeast and worms, RSV-promoted longevity also depended on SIRT1. While it remains unclear whether RSV can prolong lifespans in mammals, some studies in rodents supplemented with RSV have reported lowered body weight (BW) and fat mass, improved insulin sensitivity, lowered cholesterol levels, increased fitness, and mitochondrial biogenesis. Molecular mechanisms possibly leading to such changes include altered gene transcription and activation of SIRT1, AMP-activated kinase (AMPK), and peroxisome proliferator–activated receptor gamma coactivator 1-alpha (PPARGC1A). However, some mouse models did not benefit from RSV treatment to the same extent as others. We conducted a literature search on PubMed (15 April, 2020) for trials directly comparing RSV application to CR feeding in mice. In most studies retrieved by this systematic PubMed search, mice supplemented with RSV did not show significant reductions of BW, glucose, or insulin. Moreover, in some of these studies, RSV and CR treatments affected molecular targets differently and/or findings on RSV and CR impacts varied between trials. We discuss those RSV-induced changes in gene transcription hypothesized to partly counteract age-related alterations. Although there may be a moderate effect of RSV supplementation on parameters such as insulin sensitivity toward a more CR-like profile in mice, data are inconsistent. Likewise, RSV supplementation trials in humans report controversial findings. While we consider that RSV may, under certain circumstances, moderately mimic some aspects of CR, current evidence does not fully support its use to prevent or treat age- or obesity-related diseases.

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PGC-1α-mediated regulation of mitochondrial function and physiological implications

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2020-0005 ◽

2020 ◽

Vol 45 (9) ◽

pp. 927-936

Author(s):

Jens Frey Halling ◽

Henriette Pilegaard

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Mitochondrial Biogenesis ◽

Mitochondrial Function ◽

Current Evidence ◽

Peroxisome Proliferator ◽

Control Mechanisms ◽

Peroxisome Proliferator Activated Receptor ◽

Age Related ◽

Mitochondrial Functions

The majority of human energy metabolism occurs in skeletal muscle mitochondria emphasizing the importance of understanding the regulation of myocellular mitochondrial function. The transcriptional co-activator peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) has been characterized as a major factor in the transcriptional control of several mitochondrial components. Thus, PGC-1α is often described as a master regulator of mitochondrial biogenesis as well as a central player in regulating the antioxidant defense. However, accumulating evidence suggests that PGC-1α is also involved in the complex regulation of mitochondrial quality beyond biogenesis, which includes mitochondrial network dynamics and autophagic removal of damaged mitochondria. In addition, mitochondrial reactive oxygen species production has been suggested to regulate skeletal muscle insulin sensitivity, which may also be influenced by PGC-1α. This review aims to highlight the current evidence for PGC-1α-mediated regulation of skeletal muscle mitochondrial function beyond the effects on mitochondrial biogenesis as well as the potential PGC-1α-related impact on insulin-stimulated glucose uptake in skeletal muscle. Novelty PGC-1α regulates mitochondrial biogenesis but also has effects on mitochondrial functions beyond biogenesis. Mitochondrial quality control mechanisms, including fission, fusion, and mitophagy, are regulated by PGC-1α. PGC-1α-mediated regulation of mitochondrial quality may affect age-related mitochondrial dysfunction and insulin sensitivity.

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PPARγExpression and Function in Mycobacterial Infection: Roles in Lipid Metabolism, Immunity, and Bacterial Killing

PPAR Research ◽

10.1155/2012/383829 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 52

Author(s):

Patricia E. Almeida ◽

Alan Brito Carneiro ◽

Adriana R. Silva ◽

Patricia T. Bozza

Keyword(s):

Molecular Mechanisms ◽

Critical Role ◽

Mycobacterial Infection ◽

Receptor Activation ◽

Host Cells ◽

Current Evidence ◽

Peroxisome Proliferator ◽

Bacterial Killing ◽

Peroxisome Proliferator Activated Receptor ◽

And Function

Tuberculosis continues to be a global health threat, with drug resistance and HIV coinfection presenting challenges for its control.Mycobacterium tuberculosis, the etiological agent of tuberculosis, is a highly adapted pathogen that has evolved different strategies to subvert the immune and metabolic responses of host cells. Although the significance of peroxisome proliferator-activated receptor gamma (PPARγ) activation by mycobacteria is not fully understood, recent findings are beginning to uncover a critical role for PPARγduring mycobacterial infection. Here, we will review the molecular mechanisms that regulate PPARγexpression and function during mycobacterial infection. Current evidence indicates that mycobacterial infection causes a time-dependent increase in PPARγexpression through mechanisms that involve pattern recognition receptor activation. Mycobacterial triggered increased PPARγexpression and activation lead to increased lipid droplet formation and downmodulation of macrophage response, suggesting that PPARγexpression might aid the mycobacteria in circumventing the host response acting as an escape mechanism. Indeed, inhibition of PPARγenhances mycobacterial killing capacity of macrophages, suggesting a role of PPARγin favoring the establishment of chronic infection. Collectively, PPARγis emerging as a regulator of tuberculosis pathogenesis and an attractive target for the development of adjunctive tuberculosis therapies.

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Effect of heterozygous PPARγ deficiency and TZD treatment on insulin resistance associated with age and high-fat feeding

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00312.2002 ◽

2003 ◽

Vol 284 (3) ◽

pp. E618-E626 ◽

Cited By ~ 32

Author(s):

Philip D. G. Miles ◽

Yaacov Barak ◽

Ronald M. Evans ◽

Jerrold M. Olefsky

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Tolerance Test ◽

Hepatic Insulin Resistance ◽

Oral Glucose ◽

Peroxisome Proliferator ◽

High Fat ◽

Peroxisome Proliferator Activated Receptor ◽

Age Related ◽

Adipocyte Hypertrophy

Peroxisome proliferator-activated receptor-γ (PPARγ) is the target receptor for thiazolidinedione (TZD) compounds, which are a class of insulin-sensitizing drugs used in the treatment of type 2 diabetes. Paradoxically, however, mice deficient in PPARγ ( PPARγ+/− ) are more insulin sensitive than their wild-type (WT) littermates, not less, as would be predicted. To determine whether PPARγ deficiency could prevent the development of the insulin resistance associated with increasing age or high-fat (HF) feeding, insulin sensitivity was assessed in PPARγ+/− and WT mice at 2, 4, and 8 mo of age and in animals fed an HF diet. Because TZDs elicit their effect through PPARγ receptor, we also examined the effect of troglitazone (a TZD) in these mice. Glucose metabolism was assessed by hyperinsulinemic euglycemic clamp and oral glucose tolerance test. Insulin sensitivity declined with age for both groups. However, the decline in the PPARγ+/− animals was substantially less than that of the WT animals, such that, by 8 mo of age, the PPARγ+/− mice were markedly more insulin sensitive than the WT mice. This greater sensitivity in PPARγ+/− mice was lost with TZD treatment. HF feeding led to marked adipocyte hypertrophy and peripheral tissue and hepatic insulin resistance in WT mice but also in PPARγ+/− mice. Treatment of these mice with troglitazone completely prevented the adipocyte hypertrophy and normalized insulin action. In conclusion, PPARγ deficiency partially protects against age-related insulin resistance but does not protect against HF diet-induced insulin resistance.

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Peroxisome Proliferator-Activated Receptor Agonists: Do They Increase Cardiovascular Risk?

PPAR Research ◽

10.1155/2009/460764 ◽

2009 ◽

Vol 2009 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Ahmad Aljada ◽

Kshitij Ashwin Shah ◽

Shaker A. Mousa

Keyword(s):

Molecular Mechanisms ◽

Review Article ◽

Current Evidence ◽

Peroxisome Proliferator ◽

Cardiovascular Risks ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Agonists ◽

Record Trial ◽

Meta Analyses

Cardiovascular disease is a major cause of morbidity and mortality among people with type 2 diabetes mellitus. The peroxisome proliferator-activated receptor (PPAR) agonists have a significant role on glucose and fat metabolism. Thiazolidinediones (TZDs) are predominantly PPARγagonists, and their primary benefit appears to be the prevention of diabetic complications by improving glycemic control and lipid profile. Recently, the cardiovascular safety of rosiglitazone was brought to center stage following meta analyses and the interim analysis of the RECORD trial. Current evidence points to rosiglitazone having a greater risk of myocardial ischemic events than placebo, metformin, or sulfonylureas. This review article discusses the mechanism of action of PPAR agonists and correlates it with clinical and laboratory outcomes in the published literature. In addition, this review article attempts to discuss some of the molecular mechanisms regarding the association between TZDs therapy and the nontraditional cardiovascular risks.

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The Nutraceutical N-Palmitoylethanolamide (PEA) Reveals Widespread Molecular Effects Unmasking New Therapeutic Targets in Murine Varicocele

Nutrients ◽

10.3390/nu13030734 ◽

2021 ◽

Vol 13 (3) ◽

pp. 734

Author(s):

Pietro Antonuccio ◽

Herbert Ryan Marini ◽

Antonio Micali ◽

Carmelo Romeo ◽

Roberta Granese ◽

...

Keyword(s):

Transforming Growth Factor ◽

Therapeutic Targets ◽

Sham Operation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Pyrin Domain ◽

Age Related ◽

Extracellular Signal ◽

Morphometric Assessment

Varicocele is an age-related disease with no current medical treatments positively impacting infertility. Toll-like receptor 4 (TLR4) expression is present in normal testis with an involvement in the immunological reactions. The role of peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor, in fertility is still unclear. N-Palmitoylethanolamide (PEA), an emerging nutraceutical compound present in plants and animal foods, is an endogenous PPAR-α agonist with well-demonstrated anti-inflammatory and analgesics characteristics. In this model of mice varicocele, PPAR-α and TLR4 receptors’ roles were investigated through the administration of ultra-micronized PEA (PEA-um). Male wild-type (WT), PPAR-α knockout (KO), and TLR4 KO mice were used. A group underwent sham operation and administration of vehicle or PEA-um (10 mg/kg i.p.) for 21 days. Another group (WT, PPAR-α KO, and TLR4 KO) underwent surgical varicocele and was treated with vehicle or PEA-um (10 mg/kg i.p.) for 21 days. At the end of treatments, all animals were euthanized. Both operated and contralateral testes were processed for histological and morphometric assessment, for PPAR-α, TLR4, occludin, and claudin-11 immunohistochemistry and for PPAR-α, TLR4, transforming growth factor-beta3 (TGF-β3), phospho-extracellular signal-Regulated-Kinase (p-ERK) 1/2, and nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) Western blot analysis. Collectively, our data showed that administration of PEA-um revealed a key role of PPAR-α and TLR4 in varicocele pathophysiology, unmasking new nutraceutical therapeutic targets for future varicocele research and supporting surgical management of male infertility.

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Contribution of PGC-1α to Obesity- and Caloric Restriction-Related Physiological Changes in White Adipose Tissue

International Journal of Molecular Sciences ◽

10.3390/ijms22116025 ◽

2021 ◽

Vol 22 (11) ◽

pp. 6025

Author(s):

Masaki Kobayashi ◽

Yusuke Deguchi ◽

Yuka Nozaki ◽

Yoshikazu Higami

Keyword(s):

Adipose Tissue ◽

Caloric Restriction ◽

White Adipose Tissue ◽

Mitochondrial Gene ◽

Energy Resource ◽

Peroxisome Proliferator ◽

Physiological Changes ◽

Mitochondrial Gene Expression ◽

Peroxisome Proliferator Activated Receptor ◽

White Adipocytes

Peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) regulates mitochondrial DNA replication and mitochondrial gene expression by interacting with several transcription factors. White adipose tissue (WAT) mainly comprises adipocytes that store triglycerides as an energy resource and secrete adipokines. The characteristics of WAT vary in response to systemic and chronic metabolic alterations, including obesity or caloric restriction. Despite a small amount of mitochondria in white adipocytes, accumulated evidence suggests that mitochondria are strongly related to adipocyte-specific functions, such as adipogenesis and lipogenesis, as well as oxidative metabolism for energy supply. Therefore, PGC-1α is expected to play an important role in WAT. In this review, we provide an overview of the involvement of mitochondria and PGC-1α with obesity- and caloric restriction-related physiological changes in adipocytes and WAT.

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Diet and PPARG2 Pro12Ala Polymorphism Interactions in Relation to Cancer Risk: A Systematic Review

Nutrients ◽

10.3390/nu13010261 ◽

2021 ◽

Vol 13 (1) ◽

pp. 261

Author(s):

Lieu Tran ◽

Gerd Bobe ◽

Gayatri Arani ◽

Yang Zhang ◽

Zhenzhen Zhang ◽

...

Keyword(s):

Cancer Risk ◽

Dietary Factors ◽

Dietary Fats ◽

Current Evidence ◽

Peroxisome Proliferator ◽

Allele Polymorphism ◽

Peroxisome Proliferator Activated Receptor ◽

Complex Relation ◽

Ppar Γ ◽

Pubmed Database

Peroxisome proliferator-activated receptor-γ2 gene Pro12Ala allele polymorphism (PPARG2 Pro12Ala; rs1801282) has been linked to both cancer risk and dietary factors. We conducted the first systematic literature review of studies published before December 2020 using the PubMed database to summarize the current evidence on whether dietary factors for cancer may differ by individuals carrying C (common) and/or G (minor) alleles of the PPARG2 Pro12Ala allele polymorphism. The inclusion criteria were observational studies that investigated the association between food or nutrient consumption and risk of incident cancer stratified by PPARG2 Pro12Ala allele polymorphism. From 3815 identified abstracts, nine articles (18,268 participants and 4780 cancer cases) covering three cancer sites (i.e., colon/rectum, prostate, and breast) were included. CG/GG allele carriers were more impacted by dietary factors than CC allele carriers. High levels of protective factors (e.g., carotenoids and prudent dietary patterns) were associated with a lower cancer risk, and high levels of risk factors (e.g., alcohol and refined grains) were associated with a higher cancer risk. In contrast, both CG/GG and CC allele carriers were similarly impacted by dietary fats, well-known PPAR-γ agonists. These findings highlight the complex relation between PPARG2 Pro12Ala allele polymorphism, dietary factors, and cancer risk, which warrant further investigation.

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