CPT1A in AgRP neurons is required for sex-dependent regulation of feeding and thirst
Por:
Zagmutt, S, Mera, P, Gonzalez-Garcia, I, Ibeas, K, Romero, MD, Obri, A, Martin, B, Esteve-Codina, A, Soler-Vazquez, MC, Bastias-Perez, M, Canes, L, Auge, E, Pelegri, C, Vilaplana, J, Ariza, X, Garcia, J, Martinez-Gonzalez, J, Casals, N, Lopez, M, Palmiter, R, Sanz, E, Quintana, A, Herrero, L, Serra, D
Publicada:
25 mar 2023
Ahead of Print:
25 mar 2023
Resumen:
BackgroundFatty acid metabolism in the hypothalamus has an important role in food intake, but its specific role in AgRP neurons is poorly understood. Here, we examined whether carnitinea palmitoyltransferase 1A (CPT1A), a key enzyme in mitochondrial fatty acid oxidation, affects energy balance.MethodsTo obtain Cpt1aKO mice and their control littermates, Cpt1a((flox/flox)) mice were crossed with tamoxifen-inducible AgRPCreERT2 mice. Food intake and body weight were analyzed weekly in both males and females. At 12 weeks of age, metabolic flexibility was determined by ghrelin-induced food intake and fasting-refeeding satiety tests. Energy expenditure was analyzed by calorimetric system and thermogenic activity of brown adipose tissue. To study fluid balance the analysis of urine and water intake volumes; osmolality of urine and plasma; as well as serum levels of angiotensin and components of RAAS (renin-angiotensin-aldosterone system) were measured. At the central level, changes in AgRP neurons were determined by: (1) analyzing specific AgRP gene expression in RiboTag-Cpt1aKO mice obtained by crossing Cpt1aKO mice with RiboTag mice; (2) measuring presynaptic terminal formation in the AgRP neurons with the injection of the AAV1-EF1a-DIO-synaptophysin-GFP in the arcuate nucleus of the hypothalamus; (3) analyzing AgRP neuronal viability and spine formations by the injection AAV9-EF1a-DIO-mCherry in the arcuate nucleus of the hypothalamus; (4) analyzing in situ the specific AgRP mitochondria in the ZsGreen-Cpt1aKO obtained by breeding ZsGreen mice with Cpt1aKO mice. Two-way ANOVA analyses were performed to determine the contributions of the effect of lack of CPT1A in AgRP neurons in the sex.ResultsChanges in food intake were just seen in male Cpt1aKO mice while only female Cpt1aKO mice increased energy expenditure. The lack of Cpt1a in the AgRP neurons enhanced brown adipose tissue activity, mainly in females, and induced a substantial reduction in fat deposits and body weight. Strikingly, both male and female Cpt1aKO mice showed polydipsia and polyuria, with more reduced serum vasopressin levels in females and without osmolality alterations, indicating a direct involvement of Cpt1a in AgRP neurons in fluid balance. AgRP neurons from Cpt1aKO mice showed a sex-dependent gene expression pattern, reduced mitochondria and decreased presynaptic innervation to the paraventricular nucleus, without neuronal viability alterations.ConclusionsOur results highlight that fatty acid metabolism and CPT1A in AgRP neurons show marked sex differences and play a relevant role in the neuronal processes necessary for the maintenance of whole-body fluid and energy balance.
Filiaciones:
Zagmutt, S:
Univ Barcelona, Sch Pharm & Food Sci, Dept Biochem & Physiol, Av Joan XXIII,27-31, Barcelona 08028, Spain
Univ Barcelona, Inst Biomed, IBUB, Barcelona, Spain
Mera, P:
Univ Barcelona, Sch Pharm & Food Sci, Dept Biochem & Physiol, Av Joan XXIII,27-31, Barcelona 08028, Spain
Univ Barcelona, Inst Biomed, IBUB, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr C, Madrid, Spain
Gonzalez-Garcia, I:
Univ Santiago Compostela, Inst Invest Sanitaria, Dept Physiol, CIMUS,NeurObes Grp, Santiago De Compostela, Spain
Ibeas, K:
Univ Barcelona, Sch Pharm & Food Sci, Dept Biochem & Physiol, Av Joan XXIII,27-31, Barcelona 08028, Spain
Univ Barcelona, Inst Biomed, IBUB, Barcelona, Spain
Romero, MD:
Univ Barcelona, Sch Pharm & Food Sci, Dept Biochem & Physiol, Av Joan XXIII,27-31, Barcelona 08028, Spain
Univ Barcelona, Inst Biomed, IBUB, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr C, Madrid, Spain
Obri, A:
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Neuronal Control Metab Lab, Barcelona, Spain
Martin, B:
Barcelona Inst Sci & Technol, Ctr Genom Regulat, CNAG CRG, Barcelona 08028, Spain
Esteve-Codina, A:
Barcelona Inst Sci & Technol, Ctr Genom Regulat, CNAG CRG, Barcelona 08028, Spain
Univ Pompeu Fabra UPF, Barcelona, Spain
Soler-Vazquez, MC:
Univ Barcelona, Sch Pharm & Food Sci, Dept Biochem & Physiol, Av Joan XXIII,27-31, Barcelona 08028, Spain
Univ Barcelona, Inst Biomed, IBUB, Barcelona, Spain
Bastias-Perez, M:
Univ Barcelona, Sch Pharm & Food Sci, Dept Biochem & Physiol, Av Joan XXIII,27-31, Barcelona 08028, Spain
Univ Barcelona, Inst Biomed, IBUB, Barcelona, Spain
Canes, L:
CSIC, Inst Invest Biomed Barcelona IIBB, Barcelona, Spain
Inst Salud Carlos III, CIBER Enfermedades Cardiovasc CIBERCV, Madrid, Spain
Inst Invest Biomed St Pau IIB St Pau, Barcelona, Spain
Auge, E:
Univ Barcelona, Sch Pharm & Food Sci, Dept Biochem & Physiol, Av Joan XXIII,27-31, Barcelona 08028, Spain
Biomed Res Networking Ctr Neurodegenerat Dis CIBER, Madrid, Spain
Pelegri, C:
Univ Barcelona, Sch Pharm & Food Sci, Dept Biochem & Physiol, Av Joan XXIII,27-31, Barcelona 08028, Spain
Biomed Res Networking Ctr Neurodegenerat Dis CIBER, Madrid, Spain
Univ Barcelona, Inst Neurosci, Barcelona, Spain
Vilaplana, J:
Univ Barcelona, Sch Pharm & Food Sci, Dept Biochem & Physiol, Av Joan XXIII,27-31, Barcelona 08028, Spain
Biomed Res Networking Ctr Neurodegenerat Dis CIBER, Madrid, Spain
Univ Barcelona, Inst Neurosci, Barcelona, Spain
Ariza, X:
Inst Salud Carlos III, Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr C, Madrid, Spain
Univ Barcelona, Inst Biomed, Fac Chem, Dept Inorgan & Organ Chem,IBUB, Barcelona, Spain
Garcia, J:
Inst Salud Carlos III, Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr C, Madrid, Spain
Univ Barcelona, Inst Biomed, Fac Chem, Dept Inorgan & Organ Chem,IBUB, Barcelona, Spain
Martinez-Gonzalez, J:
CSIC, Inst Invest Biomed Barcelona IIBB, Barcelona, Spain
Inst Salud Carlos III, CIBER Enfermedades Cardiovasc CIBERCV, Madrid, Spain
Inst Invest Biomed St Pau IIB St Pau, Barcelona, Spain
Casals, N:
Inst Salud Carlos III, Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr C, Madrid, Spain
Univ Int Catalunya, Fac Med & Hlth Sci, Dept Basic Sci, Sant Cugat Del Valles, Spain
Lopez, M:
Inst Salud Carlos III, Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr C, Madrid, Spain
Univ Santiago Compostela, Inst Invest Sanitaria, Dept Physiol, CIMUS,NeurObes Grp, Santiago De Compostela, Spain
Palmiter, R:
Univ Washington, Howard Hughes Med Inst, Dept Biochem, Seattle, WA USA
Sanz, E:
Univ Autonoma Barcelona, Dept Cell Biol Physiol & Immunol, Bellaterra, Spain
Univ Autonoma Barcelona, Inst Neurociencies, Bellaterra, Spain
Quintana, A:
Univ Autonoma Barcelona, Dept Cell Biol Physiol & Immunol, Bellaterra, Spain
Univ Autonoma Barcelona, Inst Neurociencies, Bellaterra, Spain
Herrero, L:
Univ Barcelona, Sch Pharm & Food Sci, Dept Biochem & Physiol, Av Joan XXIII,27-31, Barcelona 08028, Spain
Univ Barcelona, Inst Biomed, IBUB, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr C, Madrid, Spain
Serra, D:
Univ Barcelona, Sch Pharm & Food Sci, Dept Biochem & Physiol, Av Joan XXIII,27-31, Barcelona 08028, Spain
Univ Barcelona, Inst Biomed, IBUB, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr C, Madrid, Spain
gold, Green Published, All Open Access, Gold, Green
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