Therapeutic effect of dichloroacetate against atherosclerosis via hepatic FGF21 induction mediated by acute AMPK activation

Abstract Dyslipidemia-induced atherosclerosis, which has a risk of high morbidity and mortality, can be alleviated by metabolic activation associated with mitochondrial function. The effect of dichloroacetate (DCA), a general pyruvate dehydrogenase kinase (PDK) inhibitor, on in vivo energy expenditure in ApoE−/− mice fed a western diet (WD) has not yet been investigated. WD-fed ApoE−/− mice developed atherosclerotic plaques and hyperlipidemia along with obesity, which were significantly ameliorated by DCA administration. Increased oxygen consumption was associated with heat production in the DCA-treated group, with no change in food intake or physical activity compared with those of the control. These processes were correlated with the increased gene expression of Dio2 and Ucp-1, which represents brown adipose tissue (BAT) activation, in both WD-induced atherosclerosis and high-fat-induced obesity models. In addition, we found that DCA stimulated hepatic fibroblast growth factor 21 (Fgf21) mRNA expression, which might be important for lowering lipid levels and insulin sensitization via BAT activation, in a dose- and time-dependent manner associated with serum FGF21 levels. Interestingly, Fgf21 mRNA expression was mediated in an AMP-activated protein kinase (AMPK)-dependent manner within several minutes after DCA treatment independent of peroxisome proliferator-activated receptor alpha (PPARα). Taken together, the results suggest that enhanced glucose oxidation by DCA protects against atherosclerosis by inducing hepatic FGF21 expression and BAT activation, resulting in augmented energy expenditure for heat generation.

Download Full-text

Abstract 301: Initial Increase of Klf5 and Ppara Expression After Myocardial Ischemia/Reperfusion in Mice Appears to be Critical for Survival

Circulation Research ◽

10.1161/res.119.suppl_1.301 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Christine J Pol ◽

Mesele-Christina Valenti ◽

Sarah M Schumacher ◽

Ancai Yuan ◽

Erhe Gao ◽

...

Keyword(s):

Mrna Expression ◽

Ischemia Reperfusion ◽

Pyruvate Dehydrogenase Kinase ◽

Acid Oxidation ◽

Initial Increase ◽

Peroxisome Proliferator ◽

Wild Type ◽

Peroxisome Proliferator Activated Receptor ◽

Myocardial Ischemia Reperfusion

Krüppel-like factors (KLF) have important roles in metabolism. We previously found that KLF5 is a positive transcriptional regulator of peroxisome proliferator-activated receptor α ( Ppara) , a central regulator of cardiac fatty acid oxidation (FAO). Mice with cardiomyocyte-specific Klf5 ablation ( α MHC-Klf5 -/- ) had reduced cardiac Ppara expression and FAO. At age 6-12 months these mice develop distinct cardiac dysfunction. The role of PPARα activation in I/R injury is unclear as both beneficial and detrimental effects have been reported. We aimed to study if Ppara expression changes during I/R are driven by KLF5 and explore its protective or detrimental role. Wild type mice were subjected to in vivo I/R or sham surgery. I/R resulted in an initial increase in Ppara , and its target gene pyruvate dehydrogenase kinase 4 ( Pdk4) mRNA after 2h reperfusion, followed by decreased expression after 24h reperfusion. The Ppara expression is associated with parallel changes in cardiac Klf5 mRNA expression. Concurrent, there was a decrease of cardiac FAO-related genes carnitine palmitoyl-transferase 1β ( Cpt1b), very long chain acyl-CoA dehydrogenase (Vlcad), and acyl-CoA oxidase ( Aox) in mice with I/R. To define the cell type causing the temporal changes in Klf5 and Ppara after I/R we isolated primary cardiomyocytes and fibroblasts. Our data suggest a similar effect in primary isolated cardiomyocytes only. Klf5 mRNA expression is increased after 2 hour hypoxia and normalized after 4 hour re-oxygenation in cardiomyocytes, whereas there are no changes after hypoxia/normoxia in fibroblasts. To assess the importance of cardiomyocyte KLF5 in I/R we used α MHC-Klf5 -/- mice. Interestingly, despite reduced FAO, 7 month old αMHC-Klf5 -/- mice subjected to I/R had a marked increase in mortality; 4 of 7 αMHC-Klf5 -/- mice died within the first 24h of reperfusion while no mortality was observed in age-matched wild type mice that underwent I/R. In conclusion, I/R is associated with an increase in Klf5 and Ppara in the first hours of reperfusion followed by a decrease in Klf5 and Ppara , likely accounted for by cardiomyocytes. Increased mortality for α MHC-Klf5 -/- mice with I/R injury suggests that the initial increase may be an adaptive response that is critical for survival.

Download Full-text

Glucocorticoids Regulate the Metabolic Hormone FGF21 in a Feed-Forward Loop

Molecular Endocrinology ◽

10.1210/me.2014-1259 ◽

2015 ◽

Vol 29 (2) ◽

pp. 213-223 ◽

Cited By ~ 44

Author(s):

Rucha Patel ◽

Angie L. Bookout ◽

Lilia Magomedova ◽

Bryn M. Owen ◽

Giulia P. Consiglio ◽

...

Keyword(s):

Primary Cultures ◽

Fibroblast Growth Factor 21 ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Feed Forward ◽

Feed Forward Loop ◽

Corticosterone Secretion ◽

Fgf21 Expression

Abstract Hormones such as fibroblast growth factor 21 (FGF21) and glucocorticoids (GCs) play crucial roles in coordinating the adaptive starvation response. Here we examine the interplay between these hormones. It was previously shown that FGF21 induces corticosterone levels in mice by acting on the brain. We now show that this induces the expression of genes required for GC synthesis in the adrenal gland. FGF21 also increases corticosterone secretion from the adrenal in response to ACTH. We further show that the relationship between FGF21 and GCs is bidirectional. GCs induce Fgf21 expression in the liver by acting on the GC receptor (GR). The GR binds in a ligand-dependent manner to a noncanonical GR response element located approximately 4.4 kb upstream of the Fgf21 transcription start site. The GR cooperates with the nuclear fatty acid receptor, peroxisome proliferator-activated receptor-α, to stimulate Fgf21 transcription. GR and peroxisome proliferator-activated receptor-α ligands have additive effects on Fgf21 expression both in vivo and in primary cultures of mouse hepatocytes. We conclude that FGF21 and GCs regulate each other's production in a feed-forward loop and suggest that this provides a mechanism for bypassing negative feedback on the hypothalamic-pituitary-adrenal axis to allow sustained gluconeogenesis during starvation.

Download Full-text

The Nutraceuticals and White Adipose Tissue in Browning Process

Current Nutrition & Food Science ◽

10.2174/1573401316999200731004318 ◽

2020 ◽

Vol 16 ◽

Author(s):

Melisa Siannoto ◽

Gaga Irawan Nugraha ◽

Ronny Lesmana ◽

Hanna Goenawan ◽

Vita Muniarti Tarawan ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

Current Knowledge ◽

Fibroblast Growth Factor 21 ◽

Peroxisome Proliferator ◽

Epidemic Disease ◽

Peroxisome Proliferator Activated Receptor ◽

Increase Energy Expenditure ◽

Brown Adipose ◽

Beige Adipose Tissue

Abstract: Obesity has become a prominent epidemic disease since its worldwide prevalence has shown a continuous rise over the past few decades. The primary aim of obesity treatment is to effectively reduce the intake of energy, while simultaneously increasing energy expenditure. Increasing thermogenesis is one of the methods to increase energy expenditure. Thermogenesis, which primarily occurs in brown adipose tissue, can also be produced by beige adipose tissue, through a process known as browning. The browning process has recently been attracting a great deal of attention as a potential anti-obesity agent. Many well-researched inducers of the browning process are readily available, including cold exposure, agonist β3-adrenergic, agonist peroxisome proliferator activated receptor γ, fibroblast growth factor 21, irisin and several nutraceuticals (including resveratrol, curcumin, quercetin, fish oils, green tea, etc.). This mini review summarizes the current knowledge and the latest research of some nutraceuticals that are potentially involved in the browning process

Download Full-text

Hypoxic Exposure Increases Energy Expenditure by Increasing Carbohydrate Oxidation in Mice

BioMed Research International ◽

10.1155/2020/6159407 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Yeram Park ◽

Deunsol Hwang ◽

Hun-Young Park ◽

Jisu Kim ◽

Kiwon Lim

Keyword(s):

Glucose Metabolism ◽

Energy Expenditure ◽

Pyruvate Dehydrogenase ◽

Hypoxic Condition ◽

Open Circuit ◽

Pyruvate Dehydrogenase Kinase ◽

Hypoxic Exposure ◽

Control Group ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

Aims. Hypoxic exposure improves glucose metabolism. We investigated to validate the hypothesis that carbohydrate (CHO) oxidation could increase in mice exposed to severe hypoxic conditions. Methods. Seven-week-old male ICR mice (n=16) were randomly divided into two groups: the control group (CON) was kept in normoxic condition (fraction of inspired O2=21%) and the hypoxia group (HYP) was exposed to hypoxic condition (fraction of inspired O2=12%, ≈altitude of 4,300 m). The CON group was pair-fed with the HYP group. After 3 weeks of hypoxic exposure, we measured respiratory metabolism (energy expenditure and substrate utilization) at normoxic conditions for 24 hours using an open-circuit calorimetry system. In addition, we investigated changes in carbohydrate mechanism-related protein expression, including hexokinase 2 (HK2), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase 4 (PDK4), and regulator of the genes involved in energy metabolism (peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PGC1α) in soleus muscle. Results. Energy expenditure (EE) and CHO oxidation over 24 hours were higher in the HYP group by approximately 15% and 34% (p<0.001), respectively. Fat oxidation was approximately 29% lower in the HYP group than the CON group (p<0.01). Body weight gains were significantly lower in the HYP group than in the CON group (CON vs. HYP; 1.9±0.9 vs. −0.3±0.9; p<0.001). Hypoxic exposure for 3 weeks significantly reduced body fat by approximately 42% (p<0.001). PDH and PGC1α protein levels were significantly higher in the HYP group (p<0.05). Additionally, HK2 was approximately 21% higher in the HYP group. Conclusions. Hypoxic exposure might significantly enhance CHO oxidation by increasing the expression of PDH and HK2. This investigation can be useful for patients with impaired glucose metabolism, such as those with type 2 diabetes.

Download Full-text

Increased Energy Expenditure and Protection from Diet-Induced Obesity in Mice Lacking the cGMP-Specific Phosphodiesterase PDE9

10.2337/figshare.16701997 ◽

2021 ◽

Author(s):

Ryan P. Ceddia ◽

Dianxin Liu ◽

Fubiao Shi ◽

Mark K. Crowder ◽

Sumita Mishra ◽

...

Keyword(s):

Energy Expenditure ◽

Second Messengers ◽

Diet Induced Obesity ◽

Brown Adipose ◽

Elevated Expression ◽

Obesity In Mice ◽

Ucp1 Expression ◽

Global Increase ◽

Fat Diets

Cyclic nucleotides, cAMP and cGMP, are important second messengers for the regulation of adaptive thermogenesis. Their levels are controlled not only by their synthesis but also their degradation. Since pharmacological inhibitors of cGMP-specific phosphodiesterase 9 (PDE9) can increase PKG signaling and UCP1 expression in adipocytes, we sought to elucidate the role of PDE9 on energy balance and glucose homeostasis in vivo. Mice with targeted disruption of the PDE9 gene, Pde9a, were fed nutrient matched high-fat (HFD) or low-fat diets (LFD). Pde9a‑/‑ mice were resistant to HFD induced obesity, exhibiting a global increase in energy expenditure, while brown adipose tissue (AT) had increased respiratory capacity and elevated expression of Ucp1 and other thermogenic genes. Reduced adiposity of HFD-fed Pde9a‑/‑ mice was associated with improvements in glucose handling and hepatic steatosis. Cold exposure or treatment with β-adrenergic receptor agonists markedly decreased Pde9a expression in brown AT and cultured brown adipocytes, while Pde9a‑/‑ mice exhibited a greater increase in AT browning; together suggesting that the PDE9-cGMP pathway augments classical cold-induced β-adrenergic/cAMP AT browning and energy expenditure. These findings suggest PDE9 is a previously unrecognized regulator of energy metabolism and that its inhibition may be a valuable avenue to explore for combating metabolic disease.

Download Full-text

trans-10, cis-12, but not cis-9,trans-11 CLA isomer, inhibits brown adipocyte thermogenic capacity

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00637.2001 ◽

2002 ◽

Vol 282 (6) ◽

pp. R1789-R1797 ◽

Cited By ~ 19

Author(s):

Enrique Rodrı́guez ◽

Joan Ribot ◽

Andreu Palou

Keyword(s):

Linoleic Acid ◽

Uncoupling Protein ◽

Brown Adipocyte ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Equal Concentration ◽

Brown Adipose ◽

Cla Isomers ◽

Thermogenic Capacity

Conjugated linoleic acid (CLA) is reported to have health benefits, including reduction of body fat. Previous studies have shown that brown adipose tissue (BAT) is particularly sensitive to CLA-supplemented diet feeding. Most of them use mixtures containing several CLA isomers, mainly cis-9, trans-11 and trans-10, cis-12 in equal concentration. Our aim was to characterize the separate effects of both CLA isomers on thermogenic capacity in cultured brown adipocytes. The CLA isomers showed opposite effects. Hence, on the one hand, trans-10, cis-12 inhibited uncoupling protein (UCP) 1 induction by norepinephrine (NE) and produced a decrease in leptin mRNA levels. These effects were associated with a blockage of CCAAT-enhancer-binding protein-α and peroxisome proliferator-activated receptor-γ2 mRNA expression. On the other hand, cis-9, trans-11 enhanced the UCP1 elicited by NE, an effect reported earlier for polyunsaturated fatty acids and also observed here for linoleic acid. These findings could explain, at least in part, the effects observed in vivo when feeding a CLA mixture supplemented diet as a result of the combined action of CLA isomers (reduction of adipogenesis and defective BAT thermogenesis that could be through trans-10, cis-12 and enhanced UCP1 thermogenic capacity through cis-9, trans-11).

Download Full-text

PPARγ regulates adipose triglyceride lipase in adipocytes in vitro and in vivo

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00122.2007 ◽

2007 ◽

Vol 293 (6) ◽

pp. E1736-E1745 ◽

Cited By ~ 132

Author(s):

Erin E. Kershaw ◽

Michael Schupp ◽

Hong-Ping Guan ◽

Noah P. Gardner ◽

Mitchell A. Lazar ◽

...

Keyword(s):

Protein Synthesis ◽

Adipose Tissue ◽

Lipid Metabolism ◽

Protein Synthesis Inhibitor ◽

Adipose Triglyceride Lipase ◽

Dependent Manner ◽

Triglyceride Lipase ◽

Brown Adipose

Peroxisome proliferator-activated receptor-γ (PPARγ) regulates adipocyte genes involved in adipogenesis and lipid metabolism and is the molecular target for thiazolidinedione (TZD) antidiabetic agents. Adipose triglyceride lipase (ATGL) is a recently described triglyceride-specific lipase that is induced during adipogenesis and remains highly expressed in mature adipocytes. This study evaluates the ability of PPARγ to directly regulate ATGL expression in adipocytes in vitro and in vivo. In fully differentiated 3T3-L1 adipocytes, ATGL mRNA and protein are increased by TZD and non-TZD PPARγ agonists in a dose- and time-dependent manner. Rosiglitazone-mediated induction of ATGL mRNA is rapid and is not inhibited by the protein synthesis inhibitor cycloheximide, indicating that intervening protein synthesis is not required for this effect. Rosiglitazone-mediated induction of ATGL mRNA and protein is inhibited by the PPARγ-specific antagonist GW-9662 and is also significantly reduced following siRNA-mediated knockdown of PPARγ, supporting the direct transcriptional regulation of ATGL by PPARγ. In vivo, ATGL mRNA and protein are increased by rosiglitazone treatment in white and brown adipose tissue of mice with and without obesity due to high-fat diet or leptin deficiency. Thus, PPARγ positively regulates ATGL mRNA and protein expression in mature adipocytes in vitro and in adipose tissue in vivo, suggesting a role for ATGL in mediating PPARγ's effects on lipid metabolism.

Download Full-text

Regulation of peroxisome proliferator-activated receptor-γ in liver fibrosis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00124.2006 ◽

2006 ◽

Vol 291 (5) ◽

pp. G902-G911 ◽

Cited By ~ 78

Author(s):

Liu Yang ◽

Che-Chang Chan ◽

Oh-Sang Kwon ◽

Songling Liu ◽

Jason McGhee ◽

...

Keyword(s):

Smooth Muscle ◽

Liver Injury ◽

Mrna Expression ◽

Cell Activation ◽

Stellate Cell ◽

Stellate Cells ◽

Collagen I ◽

Peroxisome Proliferator ◽

Actin Mrna

The peroxisome proliferator-activated receptors (PPARs) impart diverse cellular effects in biological systems. Because stellate cell activation during liver injury is associated with declining PPARγ expression, we hypothesized that its expression is critical in stellate cell-mediated fibrogenesis. We therefore modulated its expression during liver injury in vivo. PPARγ was depleted in rat livers by using an adenovirus-Cre recombinase system. PPARγ was overexpressed by using an additional adenoviral vector (AdPPARγ). Bile duct ligation was utilized to induce stellate cell activation and liver fibrosis in vivo; phenotypic effects (collagen I, smooth muscle α-actin, hydroxyproline content, etc.) were measured. PPARγ mRNA levels decreased fivefold and PPARγ protein was undetectable in stellate cells after culture-induced activation. During activation in vivo, collagen accumulation, assessed histomorphometrically and by hydroxyproline content, was significantly increased after PPARγ depletion compared with controls (1.28 ± 0.14 vs. 1.89 ± 0.21 mg/g liver tissue, P < 0.03). In isolated stellate cells, AdPPARγ overexpression resulted in significantly increased adiponectin mRNA expression and decreased collagen I and smooth muscle α-actin mRNA expression compared with controls. During in vivo fibrogenesis, rat livers exposed to AdPPARγ had significantly less fibrosis than controls. Collagen I and smooth muscle α-actin mRNA expression were significantly reduced in AdPPARγ-infected rats compared with controls ( P < 0.05, n = 10). PPARγ-deficient mice exhibited enhanced fibrogenesis after liver injury, whereas PPARγ receptor overexpression in vivo attenuated stellate cell activation and fibrosis. The data highlight a critical role for PPARγ during in vivo fibrogenesis and emphasize the importance of the PPARγ pathway in stellate cells during liver injury.

Download Full-text

Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure, and obesity in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1986.251.5.e576 ◽

1986 ◽

Vol 251 (5) ◽

pp. E576-E583 ◽

Cited By ~ 79

Author(s):

L. H. Storlien ◽

D. E. James ◽

K. M. Burleigh ◽

D. J. Chisholm ◽

E. W. Kraegen

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Energy Expenditure ◽

Metabolic Rate ◽

Brown Adipose Tissue ◽

Whole Body ◽

Brown Adipose ◽

Glucose Output ◽

Fat Feeding

High levels of dietary fat may contribute to both insulin resistance and obesity in humans but evidence is limited. The euglycemic clamp technique combined with tracer administration was used to study insulin action in vivo in liver and individual peripheral tissues after fat feeding. Basal and nutrient-stimulated metabolic rate was assessed by open-circuit respirometry. Adult male rats were pair-fed isocaloric diets high in either carbohydrate (69% of calories; HiCHO) or fat (59% of calories; HiFAT) for 24 +/- 1 days. Feeding of the HiFAT diet resulted in a greater than 50% reduction in net whole-body glucose utilization at midphysiological insulin levels (90-100 mU/l) due to both reduced glucose disposal and, to a lesser extent, failure to suppress liver glucose output. Major suppressive effects of the HiFAT diet on glucose uptake were found in oxidative skeletal muscles (29-61%) and in brown adipose tissue (BAT; 78-90%), the latter accounting for over 20% of the whole-body effect. There was no difference in basal metabolic rate but thermogenesis in response to glucose ingestion was higher in the HiCHO group. In contrast to their reduced BAT weight, the HiFAT group accumulated more white adipose tissue, consistent with reduced energy expenditure. HiFAT feeding also resulted in major decreases in basal and insulin-stimulated conversion of glucose to lipid in liver (26-60%) and brown adipose tissue (88-90%) with relatively less effect in white adipose (0-43%). We conclude that high-fat feeding results in insulin resistance due mainly to effects in oxidative skeletal muscle and BAT.(ABSTRACT TRUNCATED AT 250 WORDS)

Download Full-text

PRIC295, a Nuclear Receptor Coactivator, Identified from PPAR-Interacting Cofactor Complex

PPAR Research ◽

10.1155/2010/173907 ◽

2010 ◽

Vol 2010 ◽

pp. 1-16 ◽

Cited By ~ 9

Author(s):

Sean R. Pyper ◽

Navin Viswakarma ◽

Yuzhi Jia ◽

Yi-Jun Zhu ◽

Joseph D. Fondell ◽

...

Keyword(s):

Nuclear Receptor ◽

Target Genes ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Nuclear Receptor Coactivator ◽

Evolutionarily Conserved

The peroxisome proliferator-activated receptor- (PPAR) plays a key role in lipid metabolism and energy combustion. Chronic activation of PPAR in rodents leads to the development of hepatocellular carcinomas. The ability of PPAR to induce expression of its target genes depends on Mediator, an evolutionarily conserved complex of cofactors and, in particular, the subunit 1 (Med1) of this complex. Here, we report the identification and characterization of PPAR-interacting cofactor (PRIC)-295 (PRIC295), a novel coactivator protein, and show that it interacts with the Med1 and Med24 subunits of the Mediator complex. PRIC295 contains 10 LXXLL signature motifs that facilitate nuclear receptor binding and interacts with PPAR and five other members of the nuclear receptor superfamily in a ligand-dependent manner. PRIC295 enhances the transactivation function of PPAR, PPAR, and ER. These data demonstrate that PRIC295 interacts with nuclear receptors such as PPAR and functions as a transcription coactivator underin vitroconditions and may play an important role in mediating the effectsin vivoas a member of the PRIC complex with Med1 and Med24.

Download Full-text