Barbara Cannon

Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages

Attainment of a brown adipocyte cell phenotype in white adipocytes, with their abundant mitochondria and increased energy expenditure potential, is a legitimate strategy for combating obesity. The unique transcriptional regulators of the primary brown adipocyte phenotype are unknown, limiting our ability to promote brown adipogenesis over white. In the present work, we used microarray analysis strategies to study primary preadipocytes, and we made the striking discovery that brown preadipocytes demonstrate a myogenic transcriptional signature, whereas both brown and white primary preadipocytes demonstrate signatures distinct from those found in immortalized adipogenic models. We found a plausible SIRT1-related transcriptional signature during brown adipocyte differentiation that may contribute to silencing the myogenic signature. In contrast to brown preadipocytes or skeletal muscle cells, white preadipocytes express Tcf21, a transcription factor that has been shown to suppress myogenesis and nuclear receptor activity. In addition, we identified a number of developmental genes that are differentially expressed between brown and white preadipocytes and that have recently been implicated in human obesity. The interlinkage between the myocyte and the brown preadipocyte confirms the distinct origin for brown versus white adipose tissue and also represents a plausible explanation as to why brown adipocytes ultimately specialize in lipid catabolism rather than storage, much like oxidative skeletal muscle tissue.

Distinct expression of muscle-specific microRNAs (myomirs) in brown adipocytes.

MicroRNAs, a novel class of post‐transcriptional gene regulators, have been demonstrated to be involved in several cellular processes regulating the expression of protein‐coding genes. Here we examine murine white and brown primary cell cultures for differential expression of miRNAs. The adipogenesis‐related miRNA miR‐143 was highly expressed in mature white adipocytes but was low in mature brown adipocytes. Three classical “myogenic” miRNAs miR‐1, miR‐133a and miR‐206 were absent from white adipocytes but were specifically expressed both in brown pre‐ and mature adipocytes, reinforcing the concept that brown adipocytes and myocytes derive from a common cell lineage that specifies energy‐dissipating cells. Augmentation of adipocyte differentiation status with norepinephrine or rosiglitazone did not affect the expression of the above miRNAs, the expression levels of which were thus innately regulated. However, expression of the miRNA miR‐455 was enhanced during brown adipocyte differentiation, similarly to the expression pattern of the brown adipocyte differentiation marker UCP1. In conclusion, miRNAs are differentially expressed in white and brown adipocytes and may be important in defining the common precursor cell for myocytes and brown adipocytes and thus have distinct roles in energy‐storing versus energy‐dissipating cells. J. Cell. Physiol. 218: 444–449, 2009.

Altered regulation of the PINK1 locus: a link between type 2 diabetes and neurodegeneration?

Mutations in PINK1 cause the mitochon‐drial‐related neurodegenerative disease Parkinsons. Here we investigate whether obesity, type 2 diabetes, or inactivity alters transcription from the PINK1 locus. We utilized a cDNA‐array and quantitative real‐time PCR for gene expression analysis of muscle from healthy volunteers following physical inactivity, and muscle and adipose tissue from nonobese or obese subjects with normal glucose tolerance or type 2 diabetes. Functional studies of PINK1 were performed utilizing RNAinterference in cell culture models. Following inactivity, the PINK1 locus had an opposing regulation pattern (PINK1 was down‐regu‐lated while natural antisense PINK1 was up‐regulated). In type 2 diabetes skeletal muscle, all transcripts from the PINK1 locus were suppressed and gene expression correlated with diabetes status. RNA interference of PINK1 in human neuronal cell lines impaired basal glucose uptake. In adipose tissue, mitochondrial gene expression correlated with PINK1 expression although remained unaltered following siRNA knockdown of Pink1 in primary cultures of brown preadipocytes. In conclusion, regulation of the PINK1 locus, previously linked to neurodegen‐erative disease, is altered in obesity, type 2 diabetes and inactivity, while the combination of RNAi experiments and clinical data suggests a role for PINK1 in cell energetics rather than in mitochondrial biogenesis.—Scheele C., Nielsen, A. R., Walden, T. B., Sewell, D. A., Fischer, C. P., Brogan, R. J., Petrovic, N., Larsson, O., Tesch, P. A., Wennmalm, K., Hutchinson, D. S., Cannon, B., Wahlestedt C., Pedersen, B. K., Timmons J. A. Altered regulation of the PINK1 locus: a link between Type 2 diabetes and neurodegeneration? FASEB J. 21, 3653–3665 (2007)

Brown adipose tissue: molecular mechanisms controlling activity and thermogenesis

Publisher Summary This chapter describes brown adipose tissue (BAT), its molecular mechanisms controlling activity, and thermogenesis. The naturally occurring mediator of thermogenesis in the tissue, noradrenaline (NA), can interact with both alpha adrenergic and beta adrenergic receptors. However, the major fraction of the heat production of isolated cells seems to derive from beta-1 adrenergic processes. Thermogenesis in the brown fat cell is activated in vivo through nervous stimulation, and not through blood-borne agents. It is believed that the brown adipocytes possess dual innervation, both through the intercostal nerve fibers and fibers entering the tissue with the blood vessels, but innervating not only the vessels themselves, but also the adipocytes. It is clear from the studies of molecular mechanisms of BAT that an intact nervous supply and a euthyroid state are essential for recruitment of BAT. It is possible that catecholamines in themselves have a stimulatory effect on recruitment, but this has to be demonstrated convincingly. It should be remembered that sympathetic nerves can contain hormones other than catecholamines, for example co-stored peptide hormones can be present and can disappear as a result of sympathectomy. It is also important to remember the paradox of the hibernators, who seem to be able to recruit BAT without activating the tissue. Thus, chronic catecholamine stimulation does not seem to be the only pathway of recruitment.

AN ATTEMPT TO DIFFERENTIATE BETWEEN α- AND β-ADRENERGIC RESPIRATORY RESPONSES IN HAMSTER BROWN FAT CELLS

Publisher Summary This chapter discusses the roles of α- and β-adrenergic stimulation for the regulation of heat production. In an experiment described in the chapter, brown fat cells were isolated from some adult golden hamsters, which had been living at an ambient temperature of 21°C, by the use of the collagenase digestion procedure. Adrenergic effects on nerve vesicles within the tissue, and the possible influence of presynaptic receptors, are minimized by the use of isolated cells. α-receptors may affect the oxygen consumption or heat production of the isolated cells. The clarification of the biochemical pathways for α-adrenergic stimulation of brown fat cells remains a challenging problem.