David A. Lewin

Cold elicits the simultaneous induction of fatty acid synthesis and β-oxidation in murine brown adipose tissue: prediction from differential gene expression and confirmation in vivo

A survey of genes differentially expressed in the brown adipose tissue (BAT) of mice exposed to a range of environmental temperatures was carried out to identify novel genes and pathways associated with the transition of this tissue toward an amplified thermogenic state. The current report focuses on an analysis of the expression patterns of 50 metabolic genes in BAT under control conditions (22°C), cold exposure (4°C, 1 to 48 h), warm acclimation (33°C, 3 wk), or food restriction/meal feeding (animals fed the same amount as warm mice). In general, expression of genes encoding proteins involving glucose uptake and catabolism was significantly elevated in the BAT of cold‐exposed mice. The levels of mRNAs encoding proteins critical to de novo lipo‐genesis were also increased. Gene expression for enzymes associated with procurement and combustion of long chain fatty acids (LCFAs) was increased in the cold. Thus, a model was proposed in which coordinated activation of glucose uptake, fatty acid synthesis, and fatty acid combustion occurs as part of the adaptive thermogenic processes in BAT. Confirmation emerged from in vivo assessments of cold‐induced changes in BAT 2‐deoxyglucose uptake (increased 2.7‐fold), BAT lipogenesis (2.8‐fold higher), and incorporation of LCFA carboxyl‐carbon into BAT water‐soluble metabolites (elevated ~twofold). It is proposed that temperature‐sensitive regulation of distinct intracellular malo‐nyl‐CoA pool sizes plays an important role in driving this unique metabolic profile via maintenance of the lipogenic pool but diminution of the carnitine palmi‐toyltransferase 1 inhibitory pool under cold conditions.—Yu X. X., Lewin, D. A., Forrest, W. F., Adams S. H. Cold elicits the simultaneous induction of fatty acid synthesis and β‐oxidation in murine brown adipose tissue: prediction from differential gene expression and confirmation in vivo. FASEB J. 16, 155–168 (2002)

WECHE: A novel hematopoietic regulatory factor

Previously, we described AGM-derived endothelial cell lines that either inhibited or permitted the development of erythroid or B cells. We utilized a differential gene expression method to isolate a chemokine, termed WECHE, from one of these cell lines. WECHE inhibited the formation of erythroid cells but had no effect on either myeloid or B cell formation. WECHE repressed BFU-E development from either mouse fetal liver or bone marrow progenitor cells but had no effect on colony formation induced by IL-3 or IL-7. WECHE reduced HPP-CFC production from fetal liver-derived stem cells. WECHE hindered the growth of yolk sac-derived endothelial cells. WECHE was also chemotactic for bone marrow cells. Thus, WECHE is a novel chemokine that regulates hematopoietic differentiation.

Staking out novelty on the genomic frontier.

Recent advances in genomics include global assessment and classification of genome content, high-throughput biological pathway construction, systematic identification of previously unpredicted genes and the in vitro creation of novel motifs with biological function not found in nature (extra-genomic gene discovery). The ability to make global surveys of transcriptomes has given rise to fields such as pharmacogenomics and toxicogenomics. These applications of genomics technologies, with conventional drug assessment methodologies, will lead to more tolerable drugs and a better understanding of clinical populations. Integration of pathway mapping, using proteomics married to expression, will also significantly affect how new therapeutics are discovered as cross-biological cross-pathway interactions lead to novel drug targets and better predictions of drug tolerance.