ELOVL3 Is an Important Component for Early Onset of Lipid Recruitment in Brown Adipose Tissue

Abstract

During the recruitment process of brown adipose tissue, the mRNA level of the fatty acyl chain elongase Elovl3 is elevated more than 200-fold in cold-stressed mice. We have obtained Elovl3-ablated mice and report here that, although cold-acclimated Elovl3-ablated mice experienced an increased heat loss due to impaired skin barrier, they were unable to hyperrecruit their brown adipose tissue. Instead, they used muscle shivering in order to maintain body temperature. Lack of Elovl3 resulted in a transient decrease in the capacity to elongate saturated fatty acyl-CoAs into very long chain fatty acids, concomitantly with the occurrence of reduced levels of arachidic acid (C20:0) and behenic acid (C22:0) in brown adipose tissue during the initial cold stress. This effect on very long chain fatty acid synthesis could be illustrated as a decrease in the condensation activity of the elongation enzyme. In addition, warmacclimated Elovl3-ablated mice showed diminished ability to accumulate fat and reduced metabolic capacity within the brown fat cells. This points to ELOVL3 as an important regulator of endogenous synthesis of saturated very long chain fatty acids and triglyceride formation in brown adipose tissue during the early phase of the tissue recruitment.Brown adipose tissue is the only tissue that functions exclusively to combust fat for heat production (1-3). When mammals encounter cold, there is an induced synthesis of specific mRNA species in brown adipose tissue, which encode enzymes regulating energy expenditure and lipid metabolism (4 -6). Most notable is the increased mRNA level of the mitochondrial uncoupling protein 1 (UCP1), which can uncouple the mitochondrial respiratory chain and thereby dissipate heat instead of conserving energy in the form of ATP. The induction of processes needed for increased brown adipose tissue activity is referred to as brown fat recruitment.The process is controlled by norepinephrine release from sympathetic nerve endings found in the tissue (7, 8) and can roughly be divided into two major phases, depending on how the animal experiences the cold (4°C) (i.e. cold stress or cold acclimation). During the first days of cold exposure (i.e. cold stress), the major effect on brown adipose tissue is the initiation of hypertrophy, and a few days later, during the onset of cold acclimation, hyperplasia occurs (9, 10). After 4 days of cold exposure, there is a doubling in DNA amount, and after 3 weeks, a 3-fold increase is detected, which is the maximal level achieved with this degree of cold (11,12). The increase in the total amount of protein in cold-exposed mice occurs also as a two-phase phenomenon (5). The first phase is completed within 3 days, and the second phase of protein increase (i.e. during cold acclimation) is found in the tissue after 2-3 weeks of cold exposure. During these events, protein synthesis mainly reflects an increase in mRNA levels (5).During the process of identifying specific cDNA molecules corresponding to mRNA species that are induced in the brown adipose ti...

Obesity resistance and deregulation of lipogenesis in Δ6‐fatty acid desaturase ( FADS 2) deficiency

“…18:2 and c-18:3 are the preferred substrates of ELOVL5 [19]. Elovl3 expression was downregulated and thereby the synthesis of saturated VLCFA and recruitment of saturated triglycerides to BAT [20], but elovl6, which encodes the elongase of saturated C12-C16 fatty acids and also correlates positively with the severity of hepatosteatosis was overexpressed. These enzymes are major targets of SREBP1c, critically involved in the development of obesity and insulin resistance.…”

Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids

“…2). This elongation step is probably catalyzed by other endogenously expressed elongases (14,36). However, VLC-FA elongation products beyond 26:0 were detected only in Elovl4-transduced cells (Fig.…”

Retinal very long-chain PUFAs: new insights from studies on ELOVL4 protein

“…Compared with Elovl3 and Elovl5 ablated mice that grew normally and were fertile ( 125,135 ), the genetic mouse models with complete removal of functional ELOVL4 protein died at birth (28)(29)(30)(31). This has so far been attributed to the abnormalities in the skin as they cannot form a proper permeability barrier due to lack of VLC-FA (mostly saturates) and die from dehydration (28)(29)(30)(31).…”

“…The Elovl3 gene was proposed to encode an enzyme involved in biosynthesis of LC-FA in brown adipose tissue of mice exposed to cold stress. The ELOVL3 protein was proposed to be responsible for elongation of C24-C26 saturated FA and PUFA ( 125,134,135 ), based on studies from Elovl3 Ϫ / Ϫ mice.…”