NT-PGC-1α deficiency decreases mitochondrial FA oxidation in brown adipose tissue and alters substrate utilization in vivo

Abstract

Transcriptional coactivator PPAR γ coactivator (PGC)-1α and its splice variant N-terminal (NT)-PGC-1α mediate transcriptional regulation of brown adipose tissue (BAT) thermogenesis in response to changes in ambient temperature. PGC-1α is dispensable for cold-induced BAT thermogenesis as long as NT-PGC-1α is present. However, the functional significance of NT-PGC-1α in BAT has not been determined. In the present study, we generated NT-PGC-1α−/− mice to investigate the effect of NT-PGC-1α deficiency on adaptive BAT thermogenesis. At thermoneutrality, NT-PGC-1α−/− mice exhibited abnormal BAT phenotype with increased accumulation of large lipid droplets concomitant with marked downregulation of FA oxidation (FAO)-related genes. Consistent with transcriptional changes, mitochondrial FAO was significantly diminished in NT-PGC-1α−/− BAT. This alteration, in turn, enhanced glucose utilization within the NT-PGC-1α−/− BAT mitochondria. In line with this, NT-PGC-1α−/− mice had higher reliance on carbohydrates. In response to cold or β3-adrenergic receptor agonist, NT-PGC-1α−/− mice transiently exhibited lower thermogenesis but reached similar thermogenic capacities as their WT littermates. Collectively, these findings demonstrate that NT-PGC-1α is an important contributor to the maintenance of FAO capacity in BAT at thermoneutrality and provide deeper insights into the relative contributions of PGC-1α and NT-PGC-1α to temperature-regulated BAT remodeling. Transcriptional coactivator PPAR γ coactivator (PGC)-1α and its splice variant N-terminal (NT)-PGC-1α mediate transcriptional regulation of brown adipose tissue (BAT) thermogenesis in response to changes in ambient temperature. PGC-1α is dispensable for cold-induced BAT thermogenesis as long as NT-PGC-1α is present. However, the functional significance of NT-PGC-1α in BAT has not been determined. In the present study, we generated NT-PGC-1α−/− mice to investigate the effect of NT-PGC-1α deficiency on adaptive BAT thermogenesis. At thermoneutrality, NT-PGC-1α−/− mice exhibited abnormal BAT phenotype with increased accumulation of large lipid droplets concomitant with marked downregulation of FA oxidation (FAO)-related genes. Consistent with transcriptional changes, mitochondrial FAO was significantly diminished in NT-PGC-1α−/− BAT. This alteration, in turn, enhanced glucose utilization within the NT-PGC-1α−/− BAT mitochondria. In line with this, NT-PGC-1α−/− mice had higher reliance on carbohydrates. In response to cold or β3-adrenergic receptor agonist, NT-PGC-1α−/− mice transiently exhibited lower thermogenesis but reached similar thermogenic capacities as their WT littermates. Collectively, these findings demonstrate that NT-PGC-1α is an important contributor to the maintenance of FAO capacity in BAT at thermoneutrality and provide deeper insights into the relative contributions of PGC-1α and NT-PGC-1α to temperature-regulated BAT remodeling. Brown adipose tissue (BAT) is specialized in dissipating energy in the form of heat. This process, known as nonshivering thermogenesis, requires an abundant fuel supply, a high number of mitochondria, and high levels of uncoupling protein 1 (UCP1), a BAT-specific transport protein located in the inner mitochondrial membrane (IMM) (1.Cannon B. Nedergaard J. Brown adipose tissue: function and physiological significance.Physiol. Rev. 2004; 84: 277-359Crossref PubMed Scopus (4521) Google Scholar). UCP1 uncouples fuel-driven proton gradient from ATP synthesis and promotes proton leak across the IMM, thus resulting in heat production (2.Nedergaard J. Golozoubova V. Matthias A. Asadi A. Jacobsson A. Cannon B. UCP1: the only protein able to mediate adaptive non-shivering thermogenesis and metabolic inefficiency.Biochim. Biophys. Acta. 2001; 1504: 82-106Crossref PubMed Scopus (465) Google Scholar, 3.Golozoubova V. Hohtola E. Matthias A. Jacobsson A. Cannon B. Nedergaard J. Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold.FASEB J. 2001; 15: 2048-2050Crossref PubMed Scopus (358) Google Scholar). BAT not only allows rodents to maintain body temperature at temperatures below the thermoneutral zone, but also plays a role in whole-body energy balance (4.Rothwell N.J. Stock M.J. A role for brown adipose tissue in diet-induced thermogenesis.Nature. 1979; 281: 31-35Crossref PubMed Scopus (1197) Google Scholar, 5.Himms-Hagen J. Brown adipose tissue thermogenesis: interdisciplinary studies.FASEB J. 1990; 4: 2890-2898Crossref PubMed Scopus (415) Google Scholar). Adult humans also have functional BAT depots that contribute to metabolic homeostasis (6.Ouellet V. Labbe S.M. Blondin D.P. Phoenix S. Guerin B. Haman F. Turcotte E.E. Richard D. Carpentier A.C. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans.J. Clin. Invest. 2012; 122: 545-552Crossref PubMed Scopus (706) Google Scholar, 7.van der Lans A.A. Hoeks J. Brans B. Vijgen G.H. Visser M.G. Vosselman M.J. Hansen J. Jorgensen J.A. Wu J. Mottaghy F.M. et al.Cold acclimation recruits human brown fat and increases nonshivering thermogenesis.J. Clin. Invest. 2013; 123: 3395-3403Crossref PubMed Scopus (587) Google Scholar). BAT undergoes cellular remodeling in response to changes in ambient temperature. Cold-induced stimulation of β3-adrenergic receptor (β3-AR) on brown adipocyte cells leads to a marked increase in UCP1 expression/activity, mitochondrial biogenesis, intracellular lipolysis, mitochondrial FA oxidation (FAO), and de novo lipogenesis (8.Yu X.X. Lewin D.A. Forrest W. Adams S.H. Cold elicits the simultaneous induction of fatty acid synthesis and beta-oxidation in murine brown adipose tissue: prediction from differential gene expression and confirmation in vivo.FASEB J. 2002; 16: 155-168Crossref PubMed Scopus (159) Google Scholar, 9.Mottillo E.P. Balasubramanian P. Lee Y.H. Weng C. Kershaw E.E. Granneman J.G. Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic beta3-adrenergic receptor activation.J. Lipid Res. 2014; 55: 2276-2286Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 10.Sanchez-Gurmaches J. Tang Y. Jespersen N.Z. Wallace M. Martinez Calejman C. Gujja S. Li H. Edwards Y.J.K. Wolfrum C. Metallo C.M. et al.Brown fat AKT2 is a cold-induced kinase that stimulates ChREBP-mediated de novo lipogenesis to optimize fuel storage and thermogenesis.Cell Metab. 2017; 27: 195-209Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). FA metabolism plays an essential role in maximizing UCP-mediated heat production. Lipolysis-derived FAs are directed to the mitochondria, where they activate UCP1 (11.Zechner R. Kienesberger P.C. Haemmerle G. Zimmermann R. Lass A. Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores.J. Lipid Res. 2009; 50: 3-21Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar, 12.Holm C. Fredrikson G. Cannon B. Belfrage P. Hormone-sensitive lipase in brown adipose tissue: identification and effect of cold exposure.Biosci. Rep. 1987; 7: 897-904Crossref PubMed Scopus (30) Google Scholar, 13.Wang H. Hu L. Dalen K. Dorward H. Marcinkiewicz A. Russell D. Gong D. Londos C. Yamaguchi T. Holm C. et al.Activation of hormone-sensitive lipase requires two steps, protein phosphorylation and binding to the PAT-1 of lipid 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, the of uncoupling protein 1 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). FAs also to the acid and is to and and are the transport to a proton gradient for heat production (1.Cannon B. Nedergaard J. Brown adipose tissue: function and physiological significance.Physiol. Rev. 2004; 84: 277-359Crossref PubMed Scopus (4521) Google Scholar). cold exposure increases FA synthesis and storage in BAT that contributes to in lipid thus FA to with increased of FAO (8.Yu X.X. Lewin D.A. Forrest W. Adams S.H. Cold elicits the simultaneous induction of fatty acid synthesis and beta-oxidation in murine brown adipose tissue: prediction from differential gene expression and confirmation in vivo.FASEB J. 2002; 16: 155-168Crossref PubMed Scopus (159) Google Scholar, 9.Mottillo E.P. Balasubramanian P. Lee Y.H. Weng C. Kershaw E.E. Granneman J.G. Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic beta3-adrenergic receptor activation.J. Lipid Res. 2014; 55: 2276-2286Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 10.Sanchez-Gurmaches J. Tang Y. Jespersen N.Z. Wallace M. Martinez Calejman C. Gujja S. Li H. Edwards Y.J.K. Wolfrum C. Metallo C.M. et al.Brown fat AKT2 is a cold-induced kinase that stimulates ChREBP-mediated de novo lipogenesis to optimize fuel storage and thermogenesis.Cell Metab. 2017; 27: 195-209Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, J.G. that fatty acid synthesis in the brown adipose tissue of is increased in of and A J. PubMed Scopus Google Scholar, P. acid synthesis in brown adipose of temperature on the of whole-body fatty acid synthesis in brown adipose tissue and the Biophys. Acta. PubMed Scopus Google Scholar). At thermoneutral temperature where are the BAT thermogenic is (1.Cannon B. Nedergaard J. Brown adipose tissue: function and physiological significance.Physiol. Rev. 2004; 84: 277-359Crossref PubMed Scopus (4521) Google Scholar). transcriptional coactivator PPAR γ coactivator is a of adaptive BAT thermogenesis P. Wu R. M. A coactivator of to adaptive Full Text Full Text PDF PubMed Scopus Google Scholar, P. C. G. V. A. S. B. et mitochondrial and the thermogenic coactivator Full Text Full Text PDF PubMed Scopus Google Scholar). PGC-1α is stimulation and a number of to increased expression of UCP1 and mitochondrial in mitochondrial and oxidative metabolism P. Wu R. M. A coactivator of to adaptive Full Text Full Text PDF PubMed Scopus Google Scholar, P. C. G. V. A. S. B. et mitochondrial and the thermogenic coactivator Full Text Full Text PDF PubMed Scopus Google Scholar). we that of the PGC-1α gene a but functional of PGC-1α in rodents and humans Y. P. D. J. J. et a of 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). PGC-1α and NT-PGC-1α are to heat from BAT to induction of UCP1 and mitochondrial gene expression in response to cold J. Wu J. S. et in adaptive energy metabolism with in 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). In mice in PGC-1α can maintain BAT function and activate cold-induced thermogenesis NT-PGC-1α UCP1 and mitochondrial in FA the and transport in the of PGC-1α Y. P. D. J. J. et a of 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. P. S. of brown and white adipocyte the transcriptional coactivator Google Scholar, Y. Y. diet-induced brown fat thermogenesis and adipose tissue oxidative 2014; PubMed Scopus Google Scholar, V. Y. J. Y. protein is to beta3-adrenergic receptor to transcriptional and physiological of adaptive thermogenesis.J. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). present at the functional significance of NT-PGC-1α in adaptive BAT thermogenesis generated NT-PGC-1α−/− the thermogenic response to or cold agonist, we demonstrate that NT-PGC-1α is dispensable for mitochondrial and but important for mitochondrial FAO in BAT and in BAT where the capacity is with findings the relative contributions of PGC-1α and NT-PGC-1α to temperature-regulated BAT remodeling. for the was the and at the and the in with the at a temperature of a with mice at or at thermoneutrality for mice at for and to temperature was at and 1 the of cold mice at and their body was a in and for and for to and body the mice at for body and and in in the mice with body for and for and was the mice in the expenditure was as and as from mice with for an At the of BAT and white adipose tissue in the and production the at from a was to a and and the cells the into and mice to mice to a to mice that the of is in M. a line for the or of in the 7: Full Text Full Text PDF PubMed Google Scholar). of the was mice to NT-PGC-1α−/− was was for as Y. P. D. J. J. et a of 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, V. Y. J. Y. protein is to beta3-adrenergic receptor to transcriptional and physiological of adaptive thermogenesis.J. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar, P. Y. C. A. of and function protein kinase of Full Text Full Text PDF PubMed Scopus Google Scholar). expression levels of to the of mitochondrial biogenesis, mitochondrial and and their with for and as V. Y. J. Y. protein is to beta3-adrenergic receptor to transcriptional and physiological of adaptive thermogenesis.J. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). oxidation was as Y. Y. diet-induced brown fat thermogenesis and adipose tissue oxidative 2014; PubMed Scopus Google Scholar, of fatty acid oxidation in tissues and 2014; PubMed Scopus Google Scholar). 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J. et a of 2009; Full Text Full Text PDF PubMed Scopus Google and that NT-PGC-1α is to maintain BAT function and activate cold-induced thermogenesis in mice in PGC-1α J. J. P. S. of brown and white adipocyte the transcriptional coactivator Google Scholar, Y. Y. diet-induced brown fat thermogenesis and adipose tissue oxidative 2014; PubMed Scopus Google Scholar, V. Y. J. Y. protein is to beta3-adrenergic receptor to transcriptional and physiological of adaptive thermogenesis.J. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). NT-PGC-1α is for BAT function and adaptive thermogenesis, we generated mice with of A was generated to a and of the murine gene that an splice for NT-PGC-1α Y. P. D. J. J. et a of 2009; Full Text Full Text PDF PubMed Scopus Google in a the is that of NT-PGC-1α as as known as and from the V. Y. J. Y. protein is to beta3-adrenergic receptor to transcriptional and physiological of adaptive thermogenesis.J. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar, S. Wu J. et 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). was to the that in M. a line for the or of in the 7: Full Text Full Text PDF PubMed Google Scholar). resulting mice to NT-PGC-1α−/− was of from and NT-PGC-1α−/− mice of the gene was with the Y. P. D. J. J. et a of 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, V. Y. J. Y. protein is to beta3-adrenergic receptor to transcriptional and physiological of adaptive thermogenesis.J. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). PGC-1α and NT-PGC-1α in and of WT but NT-PGC-1α in NT-PGC-1α−/− mice that the an the NT-PGC-1α NT-PGC-1α at the at temperature mice at or thermoneutral temperature BAT at in levels WT and NT-PGC-1α−/− BAT In NT-PGC-1α−/− mice at exhibited abnormal BAT phenotype with increased accumulation of large lipid droplets is a with BAT was also higher in NT-PGC-1α−/− BAT with WT BAT that expression of NT-PGC-1α in brown in thermogenesis, mitochondrial FA and FA synthesis J. J. P. S. of brown and white adipocyte the transcriptional coactivator Google Scholar). thus changes in gene expression with these that for the phenotype of BAT at levels of mitochondrial UCP1 and transport WT and NT-PGC-1α−/− BAT Consistent with gene expression was in mitochondrial number that NT-PGC-1α is not for expression of mitochondrial in mitochondrial biogenesis, and uncoupling in BAT. significantly expression of with lipolysis, and FA a FA and FAO as and and in NT-PGC-1α−/− BAT FAO gene expression was also with lower levels of a FAO in FA and in mitochondrial biogenesis, or M.J. M.J. A. R. et phenotype that Clin. Invest. 2002; PubMed Scopus Google Scholar, D.P. A role for the receptor in the cellular the as a of fatty acid oxidation PubMed Scopus Google Scholar). that is of NT-PGC-1α and is enhanced NT-PGC-1α Y. P. D. J. J. et a of 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. P. S. of brown and white adipocyte the transcriptional coactivator Google Scholar, Y. Y. diet-induced brown fat thermogenesis and adipose tissue oxidative 2014; PubMed Scopus Google Scholar, V. Y. J. Y. protein is to beta3-adrenergic receptor to transcriptional and physiological of adaptive thermogenesis.J. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). these findings that expression and of is to maintain FAO gene expression in the Consistent with transcriptional changes, NT-PGC-1α−/− BAT exhibited the diminished capacity to In to FAO levels of and are in BAT R. Zimmermann R. Haemmerle G. Lass A. F. and lipolysis in lipid metabolism and Metab. 2012; 15: Full Text Full Text PDF PubMed Scopus Google lower in NT-PGC-1α−/− BAT However, in levels was not with protein levels to in and lipolysis gene expression and phosphorylation of at similar that is not in NT-PGC-1α−/− BAT. NT-PGC-1α−/− BAT expression of the NT-PGC-1α and J. J. P. S. of brown and white adipocyte the transcriptional coactivator Google the effect on and of NT-PGC-1α on lipolytic and gene expression are FAO in lipolytic and gene expression the FA lipolysis, and FA synthesis (8.Yu X.X. Lewin D.A. Forrest W. Adams S.H. Cold elicits the simultaneous induction of fatty acid synthesis and beta-oxidation in murine brown adipose tissue: prediction from differential gene expression and confirmation in vivo.FASEB J. 2002; 16: 155-168Crossref PubMed Scopus (159) Google Scholar, 9.Mottillo E.P. Balasubramanian P. Lee Y.H. Weng C. Kershaw E.E. Granneman J.G. Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic beta3-adrenergic receptor activation.J. Lipid Res. 2014; 55: 2276-2286Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 10.Sanchez-Gurmaches J. Tang Y. Jespersen N.Z. Wallace M. Martinez Calejman C. Gujja S. Li H. Edwards Y.J.K. Wolfrum C. Metallo C.M. et al.Brown fat AKT2 is a cold-induced kinase that stimulates ChREBP-mediated de novo lipogenesis to optimize fuel storage and thermogenesis.Cell Metab. 2017; 27: 195-209Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, J.G. that fatty acid synthesis in the brown adipose tissue of is increased in of and A J. PubMed Scopus Google Scholar, P. acid synthesis in brown adipose of temperature on the of whole-body fatty acid synthesis in brown adipose tissue and the Biophys. Acta. PubMed Scopus Google Scholar). This gene expression in FA metabolism was not in NT-PGC-1α−/− BAT at or NT-PGC-1α−/− brown of mitochondrial of BAT with that FA was lower in NT-PGC-1α−/− BAT with WT BAT However, the of was as a mitochondrial was higher in NT-PGC-1α−/− a in utilization FAO within the increases and the that of to of fatty acid in Full Text PDF PubMed Google Scholar). resulting in FAO the of the in NT-PGC-1α−/− In gene expression was significantly lower in NT-PGC-1α−/− BAT and the as T. E. S. F. M. S. C. C. kinase 4: regulation and in in adipose PubMed Scopus Google Scholar). in and contribute to the enhanced capacity of NT-PGC-1α−/− BAT to in the mitochondria. that and fat from NT-PGC-1α−/− mice at had adipose tissue that NT-PGC-1α a number of in thermogenesis, mitochondrial mitochondrial FA and FA synthesis in J. J. P. S. of brown and white adipocyte the transcriptional coactivator Google we the effect of NT-PGC-1α deficiency on gene expression in and NT-PGC-1α−/− exhibited the higher expression of mitochondrial transport and FAO However, these changes not to increase mitochondrial and FAO levels of and as as higher in NT-PGC-1α−/− in with an increase in lipolysis levels of and not increased but phosphorylation of at was increased in NT-PGC-1α−/− In NT-PGC-1α had on gene expression and FA metabolism in adipose tissue NT-PGC-1α is for cold-induced of BAT thermogenesis, WT and NT-PGC-1α−/− mice to cold for body temperature was NT-PGC-1α−/− mice exhibited a in body temperature WT mice of cold exposure and induction of NT-PGC-1α expression in BAT and NT-PGC-1α deficiency not the and protein levels of PGC-1α in BAT and cold-induced expression of UCP1 and are for cold-induced BAT thermogenesis V. Hohtola E. Matthias A. Jacobsson A. Cannon B. Nedergaard J. Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold.FASEB J. 2001; 15: 2048-2050Crossref PubMed Scopus (358) Google Scholar, M. A.C. is essential for adaptive thermogenesis in brown adipose Clin. Invest. 2001; PubMed Scopus Google was WT and NT-PGC-1α−/− BAT that lower thermogenic response of NT-PGC-1α−/− mice is not to induction of UCP1 and in BAT. This in to of FAO in NT-PGC-1α−/− BAT. acute cold mice can their body temperature nonshivering thermogenesis and thermogenesis. the effect of we BAT thermogenesis a agonist, a thermoneutral and that expression is to adipose tissue P. F. C.M. adipose and in Full Text PDF PubMed Google Scholar, J.G. A. and expression of the Google increase in whole-body is to the of BAT thermogenesis. NT-PGC-1α−/− mice exhibited in body and body body was WT and NT-PGC-1α−/− mice of increased in WT and NT-PGC-1α−/− However, NT-PGC-1α−/− mice exhibited a lower increase in with WT during of stimulation A of for the lower thermogenesis during the acute NT-PGC-1α−/− mice able to increase to levels to WT during the stimulation the an of metabolic fuel is to was higher in NT-PGC-1α−/− mice with WT of energy utilization of was with an increase in higher can in that NT-PGC-1α−/− BAT a glucose utilization for mitochondrial the diminished FAO at thermoneutrality, NT-PGC-1α−/− BAT remodeling in response to stimulation lipid droplets of stimulation with stimulation of increased brown lipid droplets in WT and NT-PGC-1α−/− BAT and stimulation with similar changes in expression of and mitochondrial in WT and NT-PGC-1α−/− BAT that NT-PGC-1α is not to these genes. that PGC-1α is to mediate expression of and mitochondrial genes. In with mitochondrial was WT and NT-PGC-1α−/− BAT the lower expression of FAO in NT-PGC-1α−/− acute induction of FAO gene expression in response to stimulation was WT and NT-PGC-1α−/− BAT However, FAO gene levels significantly lower in NT-PGC-1α−/− BAT with for that PGC-1α is for acute induction of FAO gene expression in response to but PGC-1α and NT-PGC-1α are for the maintenance of FAO gene expression during the BAT NT-PGC-1α deficiency had effect on of WT and NT-PGC-1α−/− exhibited similar transcriptional changes with of brown and mitochondrial FAO and and lipolytic BAT thermogenic is to maintain a body temperature in of changes in ambient temperature. Transcriptional coactivator PGC-1α and its splice variant NT-PGC-1α mediate regulation of adaptive thermogenesis the transcriptional response to changes in ambient temperature. PGC-1α and NT-PGC-1α are to heat in response to cold to induction of UCP1 and mitochondrial the in mitochondrial FAO and transport in BAT J. Wu J. S. et in adaptive energy metabolism with in 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). In mice PGC-1α are NT-PGC-1α can mediate cold-induced of the in BAT V. Y. J. Y. protein is to beta3-adrenergic receptor to transcriptional and physiological of adaptive thermogenesis.J. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). present NT-PGC-1α−/− mice that NT-PGC-1α plays a important role in FAO gene expression in response to changes in ambient temperature. NT-PGC-1α is for the maintenance of FAO gene expression in and is dispensable for acute induction of FAO gene expression in response to PGC-1α is a and its and are J. of a of mitochondrial J. Clin. PubMed Scopus Google Scholar). In NT-PGC-1α is and undergoes a increase in its Y. P. D. J. J. et a of 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, P. Y. C. A. of and function protein kinase of Full Text Full Text PDF PubMed Scopus Google Scholar). that NT-PGC-1α FAO gene expression in the thermoneutral where PGC-1α and are the acute of BAT agonist, PGC-1α is to FAO However, two are for the maintenance of FAO gene expression in the where mitochondrial FAO is we the that in FAO gene expression from levels of PGC-1α of effect of NT-PGC-1α on FAO gene expression is to that the relative of PGC-1α and NT-PGC-1α to FAO gene expression on ambient temperature. FAO plays an essential role in UCP-mediated heat production in BAT. regulation of FAO gene expression two PGC-1α and NT-PGC-1α are ambient a for brown to their capacity to changes in ambient temperature. findings that NT-PGC-1α mitochondrial in thermogenesis and in brown J. J. P. S. of brown and white adipocyte the transcriptional coactivator Google Scholar, Y. Y. diet-induced brown fat thermogenesis and adipose tissue oxidative 2014; PubMed Scopus Google Scholar, K. role for the transcriptional coactivator in the regulation of mitochondrial in brown 2017; Full Text Full Text PDF PubMed Scopus Google NT-PGC-1α deficiency not expression of thermogenic and in BAT. Transcriptional coactivator is of the but not mitochondrial and in BAT J. Wu J. S. et in adaptive energy metabolism with in 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, M. W. J. J. P. of the in mitochondrial and brown fat Metab. Full Text Full Text PDF PubMed Scopus Google PGC-1α and NT-PGC-1α a important role in cold-induced increase in mitochondrial and J. Wu J. S. et in adaptive energy metabolism with in 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, M. W. J. J. P. of the in mitochondrial and brown fat Metab. Full Text Full Text PDF PubMed Scopus Google Scholar). that gene expression is similar WT and NT-PGC-1α−/− BAT to expression of mitochondrial in and in the thermoneutral and PGC-1α to mediate acute induction of mitochondrial gene expression in the that NT-PGC-1α deficiency FAO gene expression can in to the expression of in NT-PGC-1α−/− BAT. in FA and in mitochondrial biogenesis, or M.J. M.J. A. R. et phenotype that Clin. Invest. 2002; PubMed Scopus Google Scholar). that NT-PGC-1α with and Y. P. D. J. J. et a of 2009; Full Text Full Text PDF PubMed Scopus Google and that NT-PGC-1α not only gene expression but also Y. P. D. J. J. et a of 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. P. S. of brown and white adipocyte the transcriptional coactivator Google Scholar, Y. Y. diet-induced brown fat thermogenesis and adipose tissue oxidative 2014; PubMed Scopus Google Scholar, V. Y. J. Y. protein is to beta3-adrenergic receptor to transcriptional and physiological of adaptive thermogenesis.J. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). the of expression and of for the expression of FAO in NT-PGC-1α−/− BAT. Consistent with changes, NT-PGC-1α−/− BAT exhibited the diminished capacity to FAs for mitochondrial BAT higher mitochondrial was as a a in fuel utilization that in and of thus oxidation in NT-PGC-1α−/− BAT In with NT-PGC-1α−/− mice exhibited a reliance on in with an increase in we that mice PGC-1α have a higher reliance on fat Y. Y. diet-induced brown fat thermogenesis and adipose tissue oxidative 2014; PubMed Scopus Google Scholar, V. Y. J. Y. protein is to beta3-adrenergic receptor to transcriptional and physiological of adaptive thermogenesis.J. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). NT-PGC-1α in BAT to enhanced that these at at thermoneutrality to the the in NT-PGC-1α provide for the important role of NT-PGC-1α in FAO in BAT. PGC-1α and NT-PGC-1α are and in their relative contributions to adaptive thermogenesis have been findings demonstrate that the relative of PGC-1α and NT-PGC-1α to FAO gene expression on ambient temperature. two PGC-1α and NT-PGC-1α are ambient temperature brown to their capacity to changes in ambient temperature. for and for receptor brown adipose tissue energy expenditure transport FA oxidation white adipose tissue N-terminal PPAR γ coactivator uncoupling protein 1 white adipose tissue white adipose tissue