title: Severe Brown Fat Lipoatrophy Aggravates Atherosclerotic Process in Male Mice.
abstract: Obesity is one of the major risk factors for the development of cardiovascular diseases and is characterized by abnormal accumulation of adipose tissue, including perivascular adipose tissue (PVAT). However, brown adipose tissue (BAT) activation reduces visceral adiposity. To demonstrate that severe brown fat lipoatrophy might accelerate atherosclerotic process, we generated a new mouse model without insulin receptor (IR) in BAT and without apolipoprotein (Apo)E (BAT-specific IR knockout [BATIRKO];ApoE(-/-) mice) and assessed vascular and metabolic alterations associated to obesity. In addition, we analyzed the contribution of the adipose organ to vascular inflammation. Brown fat lipoatrophy induces visceral adiposity, mainly in gonadal depot (gonadal white adipose tissue [gWAT]), severe glucose intolerance, high postprandial glucose levels, and a severe defect in acute insulin secretion. BATIRKO;ApoE(-/-) mice showed greater hypertriglyceridemia than the obtained in ApoE(-/-) and hypercholesterolemia similar to ApoE(-/-) mice. BATIRKO;ApoE(-/-) mice, in addition to primary insulin resistance in BAT, also showed a significant decrease in insulin signaling in liver, gWAT, heart, aorta artery, and thoracic PVAT. More importantly, our results suggest that severe brown fat lipoatrophy aggravates the atherosclerotic process, characterized by a significant increase of lipid depots, atherosclerotic coverage, lesion size and complexity, increased macrophage infiltration, and proinflammatory markers expression. Finally, an increase of TNF-α and leptin as well as a decrease of adiponectin by BAT, gWAT, and thoracic PVAT might also be responsible of vascular damage. Our results suggest that severe brown lipoatrophy aggravates atherosclerotic process. Thus, BAT activation might protect against obesity and its associated metabolic alterations.
authors.affiliation: Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid; Health Research Institute of San Carlos Clinic Hospital; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas 28020 Madrid, Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Gómez-Hernández
authors.affiliation: Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid; Health Research Institute of San Carlos Clinic Hospital; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas 28020 Madrid, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Beneit
authors.affiliation: Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid; Health Research Institute of San Carlos Clinic Hospital; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas 28020 Madrid, Spain.
authors.forename: Óscar
authors.initials: Ó
authors.lastname: Escribano
authors.affiliation: Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid; Health Research Institute of San Carlos Clinic Hospital; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas 28020 Madrid, Spain.
authors.forename: Sabela
authors.initials: S
authors.lastname: Díaz-Castroverde
authors.affiliation: Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid; Health Research Institute of San Carlos Clinic Hospital; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas 28020 Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: García-Gómez
authors.affiliation: Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid; Health Research Institute of San Carlos Clinic Hospital; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas 28020 Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fernández
authors.affiliation: Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid; Health Research Institute of San Carlos Clinic Hospital; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas 28020 Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Benito
mesh_terms: D052242:Adiponectin / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism; D050154:Adiposity; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology*; D015415:Biomarkers / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism; D003923:Diabetes Mellitus, Lipoatrophic / Q000150:complications* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011972:Receptor, Insulin / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D052242:Adiponectin; D001057:Apolipoproteins E; D015415:Biomarkers; D020738:Leptin; D014409:Tumor Necrosis Factor-alpha; D011972:Receptor, Insulin; D005947:Glucose