Metabolic adaptation to intermittent fasting is independent of peroxisome proliferator-activated receptor alpha
Background: Peroxisome proliferator-activated receptor alpha (PPARA) is a major regulator of fatty acid oxidation and severe hepatic steatosis occurs during acute fasting in Ppara-null mice. Thus, PPARA is considered an important mediator of the fasting response; however, its role in other fasting r...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-01-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877817306440 |
| _version_ | 1819125229110165504 |
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| author | Guolin Li Chad N. Brocker Tingting Yan Cen Xie Kristopher W. Krausz Rong Xiang Frank J. Gonzalez |
| author_facet | Guolin Li Chad N. Brocker Tingting Yan Cen Xie Kristopher W. Krausz Rong Xiang Frank J. Gonzalez |
| author_sort | Guolin Li |
| collection | DOAJ |
| description | Background: Peroxisome proliferator-activated receptor alpha (PPARA) is a major regulator of fatty acid oxidation and severe hepatic steatosis occurs during acute fasting in Ppara-null mice. Thus, PPARA is considered an important mediator of the fasting response; however, its role in other fasting regiments such as every-other-day fasting (EODF) has not been investigated. Methods: Mice were pre-conditioned using either a diet containing the potent PPARA agonist Wy-14643 or an EODF regimen prior to acute fasting. Ppara-null mice were used to assess the contribution of PPARA activation during the metabolic response to EODF. Livers were collected for histological, biochemical, qRT-PCR, and Western blot analysis. Results: Acute fasting activated PPARA and led to steatosis, whereas EODF protected against fasting-induced hepatic steatosis without affecting PPARA signaling. In contrast, pretreatment with Wy-14,643 did activate PPARA signaling but did not ameliorate acute fasting-induced steatosis and unexpectedly promoted liver injury. Ppara ablation exacerbated acute fasting-induced hypoglycemia, hepatic steatosis, and liver injury in mice, whereas these detrimental effects were absent in response to EODF, which promoted PPARA-independent fatty acid metabolism and normalized serum lipids. Conclusions: These findings indicate that PPARA activation prior to acute fasting cannot ameliorate fasting-induced hepatic steatosis, whereas EODF induced metabolic adaptations to protect against fasting-induced steatosis without altering PPARA signaling. Therefore, PPARA activation does not mediate the metabolic adaptation to fasting, at least in preventing acute fasting-induced steatosis. Keywords: PPARA, PPARalpha, Intermittent fasting, Every-other-day fasting, Steatosis, Adaptive fasting response |
| first_indexed | 2024-12-22T07:36:49Z |
| format | Article |
| id | doaj.art-35757cff30c74476b1d7c79746c90264 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-22T07:36:49Z |
| publishDate | 2018-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-35757cff30c74476b1d7c79746c902642022-12-21T18:33:51ZengElsevierMolecular Metabolism2212-87782018-01-0178089Metabolic adaptation to intermittent fasting is independent of peroxisome proliferator-activated receptor alphaGuolin Li0Chad N. Brocker1Tingting Yan2Cen Xie3Kristopher W. Krausz4Rong Xiang5Frank J. Gonzalez6Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Laboratory of Aging Biochemistry, College of Life Sciences, Hunan Normal University, Changsha 410081, China; The Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China; Corresponding author. Laboratory of Aging Biochemistry, College of Life Sciences, Hunan Normal University, Changsha 410081, China.Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USALaboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USALaboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USALaboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAThe State Key Laboratory of Medical Genetics & School of Life Sciences, Central South University, Changsha 41001, ChinaLaboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Corresponding author. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.Background: Peroxisome proliferator-activated receptor alpha (PPARA) is a major regulator of fatty acid oxidation and severe hepatic steatosis occurs during acute fasting in Ppara-null mice. Thus, PPARA is considered an important mediator of the fasting response; however, its role in other fasting regiments such as every-other-day fasting (EODF) has not been investigated. Methods: Mice were pre-conditioned using either a diet containing the potent PPARA agonist Wy-14643 or an EODF regimen prior to acute fasting. Ppara-null mice were used to assess the contribution of PPARA activation during the metabolic response to EODF. Livers were collected for histological, biochemical, qRT-PCR, and Western blot analysis. Results: Acute fasting activated PPARA and led to steatosis, whereas EODF protected against fasting-induced hepatic steatosis without affecting PPARA signaling. In contrast, pretreatment with Wy-14,643 did activate PPARA signaling but did not ameliorate acute fasting-induced steatosis and unexpectedly promoted liver injury. Ppara ablation exacerbated acute fasting-induced hypoglycemia, hepatic steatosis, and liver injury in mice, whereas these detrimental effects were absent in response to EODF, which promoted PPARA-independent fatty acid metabolism and normalized serum lipids. Conclusions: These findings indicate that PPARA activation prior to acute fasting cannot ameliorate fasting-induced hepatic steatosis, whereas EODF induced metabolic adaptations to protect against fasting-induced steatosis without altering PPARA signaling. Therefore, PPARA activation does not mediate the metabolic adaptation to fasting, at least in preventing acute fasting-induced steatosis. Keywords: PPARA, PPARalpha, Intermittent fasting, Every-other-day fasting, Steatosis, Adaptive fasting responsehttp://www.sciencedirect.com/science/article/pii/S2212877817306440 |
| spellingShingle | Guolin Li Chad N. Brocker Tingting Yan Cen Xie Kristopher W. Krausz Rong Xiang Frank J. Gonzalez Metabolic adaptation to intermittent fasting is independent of peroxisome proliferator-activated receptor alpha Molecular Metabolism |
| title | Metabolic adaptation to intermittent fasting is independent of peroxisome proliferator-activated receptor alpha |
| title_full | Metabolic adaptation to intermittent fasting is independent of peroxisome proliferator-activated receptor alpha |
| title_fullStr | Metabolic adaptation to intermittent fasting is independent of peroxisome proliferator-activated receptor alpha |
| title_full_unstemmed | Metabolic adaptation to intermittent fasting is independent of peroxisome proliferator-activated receptor alpha |
| title_short | Metabolic adaptation to intermittent fasting is independent of peroxisome proliferator-activated receptor alpha |
| title_sort | metabolic adaptation to intermittent fasting is independent of peroxisome proliferator activated receptor alpha |
| url | http://www.sciencedirect.com/science/article/pii/S2212877817306440 |
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