Elevated circulating fatty acid concentration is a hallmark of insulin resistance and is at least in part attributed to the action of adipose tissue-derived tumor necrosis factor-␣ (TNF-␣) on lipolysis. Cell death-inducing DFFA (DNA fragmentation factor-␣)-like effector A (CIDEA) belongs to a family of proapoptotic proteins that has five known members in humans and mice. The action of CIDEA is unknown, but CIDEA-null mice are resistant to obesity and diabetes. We investigated CIDEA in adipose tissue of obese and lean humans and mice. The mRNA was expressed in white human fat cells and in brown mouse adipocytes. The adipose mRNA expression of CIDEA in mice was not influenced by obesity. However, CIDEA expression was decreased twofold in obese humans and normalized after weight reduction. Low adipose CIDEA expression was associated with several features of the metabolic syndrome. Human adipocyte depletion of CIDEA by RNA interference stimulated lipolysis and increased TNF-␣ secretion by a posttranscriptional effect. Conversely, TNF-␣ treatment decreased adipocyte CIDEA expression via the mitogen-activated protein kinase c-Jun NH 2 -terminal kinase. We propose an important and human-specific role for CIDEA in lipolysis regulation and metabolic complications of obesity, which is at least in part mediated by cross-talk between CIDEA and TNF-␣. Diabetes 54:1726 -1734, 2005

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...

We have created P1 artificial chromosome transgenic mice expressing the human mitochondrial superoxide dismutase 2 (SOD2) and thus generated mice with a physiologically controlled augmentation of SOD2 expression leading to increased SOD2 enzyme activities and lowered superoxide levels. In the transgenic mice, effects on mitochondrial function such as enhanced oxidative capacity and greater resistance against inducers of mitochondrial permeability were observed. Superoxide in the mitochondrial matrix has been proposed to activate uncoupling proteins (UCPs), thus providing a feedback mechanism that will lower respiratory chain superoxide production by increasing a proton leak across the inner mitochondrial membrane. However, UCP1 and UCP3 activities and mitochondrial ATP production rates were not altered in isolated mitochondria from SOD2 transgenic mice, despite lowered superoxide levels. Globally, the transgenic mice displayed normal resting metabolic rates, indicating an absence of effect on any UCP activities, and normal oxygen consumption responses after norepinephrine injection. These results strongly suggest that endogenously generated matrix superoxide does not regulate UCP activity and in vivo energy expenditure.

Mice with a dominant-negative peroxisome proliferator-activated receptor gamma (PPARgamma) mutation (P465L) unexpectedly had normal amounts of adipose tissue. Here, we investigate the adipose tissue of the PPARgamma P465L mouse in detail. Microscopic analysis of interscapular adipose tissue of P465L PPARgamma mice revealed brown adipocytes with larger unilocular lipid droplets, indicative of reduced thermogenic capacity. Under conditions of cold exposure, the brown adipose tissue of the PPARgamma P465L mice was less active, a fact reflected in decreased uncoupling protein 1 levels. Analysis of the white adipocytes confirmed their normal cytoarchitecture and development, yet classical white adipose depots of the P465L PPARgamma mice had a striking reduction in brown adipocyte recruitment, a finding supported by reduced expression of UCP1 in the perigonadal adipose depot. Taken together, these data suggest that whole animal impairment of PPARgamma alters the cellular composition of the adipose organ to a more "white" adipose phenotype. Physiologically, this impairment in brown adipocyte recruitment is associated with decreased nonshivering thermogenic capacity after cold acclimation as revealed by norepinephrine responsiveness. Our results indicate that maintenance of oxidative brown-like adipose tissue is more dependent on PPARgamma function for development than white adipose tissue, an observation that may be relevant when considering PPARgamma-dependent strategies for the treatment of obesity.