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Brown Fat Controls – PRDM16 and Bone Morphogenetic Protein 7

« Back to Volume 25, Issue 1, June 2009 - Table of Contents

Adipocytes are cells that store fats as triglycerides. White fat cells (WFC) store fats within one large, cell-filling lipid droplet. After readily available energy sources have been exhausted, the WFC hydrolyzes triglycerides and exports fatty acids to be utilized as fuel by other cells.¹ Brown fat cells (BFC) store lipids in multiple small droplets, have a large number of mitochondria (that stain brown), and actively hydrolyze triglycerides to fatty acids which are then oxidized to produce heat. The BFC is able to oxidize fatty acids, because it expresses uncoupling protein 1 (UCP1, chromosome 4q31, OMIM 113730) that, in association with its co-factor (coenzyme Q), allows protons to “leak” across the inner mitochondrial membrane thereby diverting energy from ATP synthesis to (non-shivering) thermogenesis. Adipocytes are derived from a mesenchymal precursor stem cell that also gives rise to osteoblasts, chondroblasts, myoblasts, and fibroblasts. An osteoblast can be transformed to an adipocyte if Pparγ2 (peroxisome proliferator-activated receptor γ2) is expressed, while an adipocyte can be converted to an osteoblast if Runx2 is expressed.² In the presence of a β-adrenergic stimulus, a WFC can be transformed into a BFC - both morphologically and functionally. WFCs are found subcutaneously and intra-abdominally. Foci of BFCs are more abundant in infants but are also present in adults and are distinct from those BFCs that are sparsely interspersed among WFCs. It has long been assumed that the WFC and BFC arise from the same precursor cell.³

Searle et al now demonstrated that the BFC is actually derived from a precursor cell that differentiates into either a skeletal myocyte if it expresses a myogenic determining factor (eg, Myf5) or into a BFC if it expresses Prdm16 (Proline rich domain-containing protein 16, chromosome 1p36.3, OMIM 605557) and Pparγ2 (Figure 1). Depleting BFC precursor cells of PRDM16 in vitro resulted in their differentiation into myocytes morphologically and functionally, as these cells expressed myogenic genes rather than genes characteristic of BFCs. “Knock-in” of Prdm16 into committed myoblasts led to their differentiation into BFCs morphologically and by expression of BFC genes. The investigators further demonstrated that the BFC that arose from the WFC in response to β-adrenergic stimulation was not derived from a myogenic precursor cell. Although there are zinc fingers within the structure of PRDM16, it does not bind to DNA but rather to other intracellular proteins. Binding of PRDM16 to PPARγ stimulates the transcriptional activity of PPARγ and BFC differentiation from the myogenic precursor cell. The authors concluded that the primary BFC is derived from a precursor cell that can differentiate either into either a myocyte or a BFC.

Figure 1. Paths to muscle and fat.
Skeletal myocytes and brown adipocytes derive from a common precursor cell that expresses the transcription factor Myf5. White adipocytes derive from a Myf5-negative precursor, as do brown adipocyte–like cells that appear in white fate deposits after adrenergic stimulation. These distinct cell types play very different roles in physiology.

Reprinted with permission Lazar MA. Science. 2008;321:1048-1049.

Tseng et al complement the findings of Searle et al by demonstrating that bone morphogenetic protein 7 (BMP7, chromosome 20, OMIM 112267) can also induce BFC differentiation by directing mesenchymal precursor cells to the BFC differentiation pathway. It does so by inducing expression of PRDM16 and PPARγ-coactivator-1α, a co-factor for PPARγ.

Seale P, Bjork B, Yang W, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008;454:961-967.

Tseng YH, Kokkotou E, Schulz TJ, et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature. 2008;454:1000-1004.

First Editor’s Comment

Myocytes and BFCs arise from a common precursor cell, this links the oxidative function of these 2 cell types, and perhaps provides a reason why BFCs primarily catabolize rather than store lipids. Understanding the pathway that leads to BFC development and directed oxidation of fatty acids to thermogenesis rather that to energy generation holds the potential promise for the development of drugs (perhaps agonists of BMP7) that may be able to stimulate PRDM16 activity and BFC generation and increase dissipation of fat stores. Might agonists or antagonists of this pathway even be of use in clinical conditions in which control of core body temperature is indicated?

Allen W. Root, MD

Second Editor’s Comment

A recent paper published in the New England Journal of Medicine highlighted the cold-activated brown adipose tissue in healthy men.⁴ An accompanying editorial highlighted the pathophysiology of this tissue and the potential implication for stimulating energy expenditure (Figure 2).⁵ These 2 papers proposed the concept of target interventions—pharmacological and environmental—aimed at modulating energy metabolism. Wouldn’t it be great if lowering the thermostat could help prevent and treat obesity?

Fima Lifshitz, MD

Figure 2. The Activation of Brown Adipose Tissue.
Stimulation of β₃-adrenergic receptors leads to the dramatic increase in the intracellular concentration of triiodothyronine (T₃) by means of the type 2 5' deiodinase (D2); T₃ in turn stimulates the transcription of uncoupling protein 1 (UCP1), which causes the leakage of protons from the inner membrane of the mitochondria, hence dissipating energy in the form of heat. The abbreviation cAMP denotes cyclic adenosine monophosphate, CRE cAMP response element, T₄ thyroxine, and TRE thyroid hormone response element.

References - (linked to )

Lazar MA. How now, brown fat? Science. 2008;321:1048-1049.
Aubin JE, Lian J, Stein G. Bone formation: Maturation and functional activities of osteoblast lineage cells. in Favus MJ (ed). Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 6th ed. Washington, D.C: American Society for Bone and Mineral Research; 2006, 20-29.
Gesta S, Tseng YH, Kahn CR.. Developmental origin of fat: Tracking obesity to its source. Cell. 2007;131:242-256.
van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009;360:1500-1508.
Celi F. Brown adipose tissue. N Engl J Med. 2009;360:1553-1556.

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Last Updated: 6/12/2009