Mitochondrial 2,4-dienoyl-CoA reductase (Decr) deficiency and impairment of thermogenesis in mouse brown adipose tissue

Abstract

A large number of studies have demonstrated significance of polyunsaturated fatty acids (PUFAs) for human health. However, many aspects on signals translating PUFA-sensing into body homeostasis have remained enigmatic. To shed light on PUFA physiology, we have generated a mouse line defective in mitochondrial dienoyl-CoA reductase (Decr), which is a key enzyme required for β-oxidation of PUFAs. Previously, we have shown that these mice, whose oxidation of saturated fatty acid is intact but break-down of unsaturated fatty acids is blunted, develop severe hypoglycemia during metabolic stresses and fatal hypothermia upon acute cold challenge. In the current work, indirect calorimetry and thermography suggested that cold intolerance of Decr −/− mice is due to failure in maintaining appropriate heat production at least partly due to failure of brown adipose tissue (BAT) thermogenesis. Magnetic resonance imaging, electron microscopy, mass spectrometry and biochemical analysis showed attenuation in activation of lipolysis despite of functional NE-signaling and inappropriate expression of genes contributing to thermogenesis in iBAT when the Decr −/− mice were exposed to cold. We hypothesize that the failure in turning on BAT thermogenesis occurs due to accumulation of unsaturated long-chain fatty acids or their metabolites in Decr −/− mice BAT suppressing down-stream propagation of NE-signaling.

Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis

“…Human DECR1 deficiency is lethal, with patients exhibiting hypocarnitinemia, decreased cellular oxygen consumption, increased lactic acidosis, and unusual accumulation of FA intermediates in urine and blood due to incomplete β-oxidation ( Roe et al, 1990 ; Houten et al, 2014 ). DECR1-null mice exhibit impaired lipid metabolism, hypoglycemia and activation of ketogenesis, and cold intolerance ( Miinalainen et al, 2009 ; Mäkelä et al, 2019 ). These phenotypes highlight the critical role of DECR1 in lipid metabolism.…”

“…CPT1 inhibition would suppress β-oxidation of all long FA species (saturated FA, MUFA and PUFA), whilst in contrast DECR1 is specific for PUFA. Homozygous CPT1 deficiency, of either the liver or muscle isoform, is lethal in mice ( Nyman et al, 2005 ; Ji et al, 2008 ; Haynie et al, 2014 ), but Decr1 −/− mice are viable, and clinical symptoms arose only after metabolic stress ( Miinalainen et al, 2009 ; Mäkelä et al, 2019 ). The marked overexpression of DECR1 in prostate tumors across multiple clinical cohorts, potentially coupled to PUFA-related dietary interventions, may lend further selectivity to targeting strategies.…”

Selection Signature and CRISPR/Cas9-Mediated Gene Knockout Analyses Reveal ZC3H10 Involved in Cold Adaptation in Chinese Native Cattle

“…Unsaturated fatty acids have stimulatory effects on energy expenditure [ 19 ]. The synthesis and decomposition of unsaturated fatty acids are closely related to heat production [ 20 ]. The PPAR signaling pathway participates in the regulation of lipid metabolism, energy homeostasis, and cell differentiation, and is related to many metabolic diseases, such as metabolic syndrome, dyslipidemia, and diabetes [ 21 ].…”

DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis

“…CPT1 inhibition would suppress β -oxidation of all long FA species (saturated FA, MUFA and PUFA), whilst in contrast DECR1 is specific for PUFA. Homozygous CPT1 deficiency, of either the liver or muscle isoform, is lethal in mice (72-74), but Decr1 −/− mice are viable, and clinical symptoms arose only after metabolic stress (52,53). The marked overexpression of DECR1 in prostate tumors across multiple clinical cohorts, potentially coupled to PUFA-related dietary interventions, may lend further selectivity to targeting strategies.…”