Loss of macrophage fatty acid oxidation does not potentiate systemic metabolic dysfunction

Gonzalez-Hurtado, Elsie; Lee, Jieun; Choi, Joseph; Alpergin, Ebru S. Selen; Collins, Samuel; Horton, Maureen R.; Wolfgang, Michael J.

doi:10.1152/ajpendo.00408.2016

Cited by 31 publications

(32 citation statements)

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“…Our work confirms previous reports that IL4 increases macrophage respiration (Vats et al 2006). Those studies of Balb/c macrophages chronically (96 h) treated with IL4 showed a role of PPARγ in fatty acid oxidation to promote oxidative phosphorylation in AA (Vats et al 2006;Odegaard et al 2007), while other studies suggest that fatty acid oxidation is not required for AA of C57Bl/6 macrophages (Nomura et al 2016;Gonzalez-Hurtado et al 2017). More recent studies demonstrate that glutamine metabolism is required for AA (Jha et al 2015), likely via metabolism to αKG (Liu et al 2017;Palmieri et al 2017).…”

Section: Discussionsupporting

confidence: 90%

PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism

et al. 2018

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The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that peritoneal macrophage respiration is enhanced by rosiglitazone, an activating PPARγ ligand, in a PPARγ-dependent manner. Moreover, PPARγ is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPARγ dramatically affects the oxidation of glutamine. Both glutamine and PPARγ have been implicated in alternative activation (AA) of macrophages, and PPARγ was required for interleukin 4 (IL4)-dependent gene expression and stimulation of macrophage respiration. Indeed, unstimulated macrophages lacking PPARγ contained elevated levels of the inflammation-associated metabolite itaconate and express a proinflammatory transcriptome that, remarkably, phenocopied that of macrophages depleted of glutamine. Thus, PPARγ functions as a checkpoint, guarding against inflammation, and is permissive for AA by facilitating glutamine metabolism. However, PPARγ expression is itself markedly increased by IL4. This suggests that PPARγ functions at the center of a feed-forward loop that is central to AA of macrophages.

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Section: Discussionsupporting

confidence: 90%

PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism

et al. 2018

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“…Analysis of gene expression was carried out in a CFX Connect Real-Time System (Bio-Rad). For each gene, mRNA expression was calculated as 2ˆdeltaCT relative to Rpl22 and 18s expression [13] . Primers and gene information are provided in Table S1 .…”

Section: Methodsmentioning

confidence: 99%

Fatty acid oxidation is required for active and quiescent brown adipose tissue maintenance and thermogenic programing

Gonzalez-Hurtado

Lee

Choi

et al. 2018

Molecular Metabolism

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ObjectiveTo determine the role of fatty acid oxidation on the cellular, molecular, and physiologic response of brown adipose tissue to disparate paradigms of chronic thermogenic stimulation.MethodsMice with an adipose-specific loss of Carnitine Palmitoyltransferase 2 (Cpt2A−/−), that lack mitochondrial long chain fatty acid β-oxidation, were subjected to environmental and pharmacologic interventions known to promote thermogenic programming in adipose tissue.ResultsChronic administration of β3-adrenergic (CL-316243) or thyroid hormone (GC-1) agonists induced a loss of BAT morphology and UCP1 expression in Cpt2A−/− mice. Fatty acid oxidation was also required for the browning of white adipose tissue (WAT) and the induction of UCP1 in WAT. In contrast, chronic cold (15 °C) stimulation induced UCP1 and thermogenic programming in both control and Cpt2A−/− adipose tissue albeit to a lesser extent in Cpt2A−/− mice. However, thermoneutral housing also induced the loss of UCP1 and BAT morphology in Cpt2A−/− mice. Therefore, adipose fatty acid oxidation is required for both the acute agonist-induced activation of BAT and the maintenance of quiescent BAT. Consistent with this data, Cpt2A−/− BAT exhibited increased macrophage infiltration, inflammation and fibrosis irrespective of BAT activation. Finally, obese Cpt2A−/− mice housed at thermoneutrality exhibited a loss of interscapular BAT and were refractory to β3-adrenergic-induced energy expenditure and weight loss.ConclusionMitochondrial long chain fatty acid β-oxidation is critical for the maintenance of the brown adipocyte phenotype both during times of activation and quiescence.

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“…Steady-state 1 H NMR Spectroscopy was done as previously described(Gonzalez-Hurtado et al, 2017; Selen et al, 2015). 13 C NMR spectra were collected using a zgpg30 pulse program on a 500MHz Bruker Avance III (Bruker, Germany).…”

Section: Methodsmentioning

confidence: 99%

Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance

et al. 2017

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SUMMARY The liver has a large capacity for mitochondrial fatty acid β-oxidation, which is critical for systemic metabolic adaptations such as gluconeogenesis and ketogenesis. To understand the role of hepatic fatty acid oxidation in response to a chronic high fat diet (HFD), we generated mice with a liver-specific deficiency of mitochondrial long chain fatty acid β-oxidation (Cpt2L−/− mice). Paradoxically, Cpt2L−/− mice were resistant to HFD-induced obesity and glucose intolerance with an absence of liver damage, although they exhibited serum dyslipidemia, hepatic oxidative stress and systemic carnitine deficiency. Feeding a HFD induced hepatokines in mice with a loss of hepatic fatty acid oxidation that enhanced systemic energy expenditure and suppressed adiposity. Additionally, the suppression in hepatic gluconeogenesis was sufficient to improve HFD-induced glucose intolerance. These data show that inhibiting hepatic fatty acid oxidation results in a systemic hormetic response that protects mice from HFD-induced obesity and glucose intolerance.

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Loss of macrophage fatty acid oxidation does not potentiate systemic metabolic dysfunction

Cited by 31 publications

References 50 publications

PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism

PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism

Fatty acid oxidation is required for active and quiescent brown adipose tissue maintenance and thermogenic programing

Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance

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