抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-γ co-activator-1 α (PGC1-α). Here we show in mouse that PGC1-α expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise.

/pdf/a-pgc1-a-dependent-myokine-that-drives-brown-fat-like-2kbx57f12b.pdf

A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis

https://www.mergenmetz.nl/menn/wp-content/uploads/2012/07/Insirine-of-bewegen-artikel-in-Cell.pdf

Beige Adipocytes Are a Distinct Type of Thermogenic Fat Cell in Mouse and Human

Adipose tissue, best known for its role in fat storage, can also suppress weight gain and metabolic disease through the action of specialized, heat-producing adipocytes. Brown adipocytes are located in dedicated depots and express constitutively high levels of thermogenic genes, whereas inducible 'brown-like' adipocytes, also known as beige cells, develop in white fat in response to various activators. The activities of brown and beige fat cells reduce metabolic disease, including obesity, in mice and correlate with leanness in humans. Many genes and pathways that regulate brown and beige adipocyte biology have now been identified, providing a variety of promising therapeutic targets for metabolic disease.

/pdf/brown-and-beige-fat-development-function-and-therapeutic-5dt1btf02v.pdf

Brown and beige fat: development, function and therapeutic potential

https://www.cell.com/cell/pdf/S0092-8674(13)01546-8.pdf

What We Talk About When We Talk About Fat

The white adipose organ is composed of both subcutaneous and several intra-abdominal depots. Excess abdominal adiposity is a major risk factor for metabolic disease in rodents and humans, while expansion of subcutaneous fat does not carry the same risks. Brown adipose produces heat as a defense against hypothermia and obesity, and the appearance of brown-like adipocytes within white adipose tissue depots is associated with improved metabolic phenotypes. Thus, understanding the differences in cell biology and function of these different adipose cell types and depots may be critical to the development of new therapies for metabolic disease. Here, we found that Prdm16, a brown adipose determination factor, is selectively expressed in subcutaneous white adipocytes relative to other white fat depots in mice. Transgenic expression of Prdm16 in fat tissue robustly induced the development of brown-like adipocytes in subcutaneous, but not epididymal, adipose depots. Prdm16 transgenic mice displayed increased energy expenditure, limited weight gain, and improved glucose tolerance in response to a high-fat diet. shRNA-mediated depletion of Prdm16 in isolated subcutaneous adipocytes caused a sharp decrease in the expression of thermogenic genes and a reduction in uncoupled cellular respiration. Finally, Prdm16 haploinsufficiency reduced the brown fat phenotype in white adipose tissue stimulated by β-adrenergic agonists. These results demonstrate that Prdm16 is a cell-autonomous determinant of a brown fat–like gene program and thermogenesis in subcutaneous adipose tissues.

/pdf/prdm16-determines-the-thermogenic-program-of-subcutaneous-2tbv72gzdv.pdf

Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice

Satellite cells purified from adult skeletal muscle can participate extensively in muscle regeneration and can also re-populate the satellite cell pool, suggesting that they have direct therapeutic potential for treating degenerative muscle diseases1,2. The paired-box transcription factor Pax7 is required for satellite cells to generate committed myogenic progenitors3. In this study we undertook a multi-level approach to define the role of Pax7 in satellite cell function. Using comparative microarray analysis, we identified several novel and strongly regulated targets; in particular, we identified Myf5 as a gene whose expression was regulated by Pax7. Using siRNA, fluorescence-activated cell sorting (FACS) and chromatin immunoprecipitation (ChIP) studies we confirmed that Myf5 is directly regulated by Pax7 in myoblasts derived from satellite cells. Tandem affinity purification (TAP) and mass spectrometry were used to purify Pax7 together with its co-factors. This revealed that Pax7 associates with the Wdr5–Ash2L–MLL2 histone methyltransferase (HMT) complex that directs methylation of histone H3 lysine 4 (H3K4, refs 4–10). Binding of the Pax7–HMT complex to Myf5 resulted in H3K4 tri-methylation of surrounding chromatin. Thus, Pax7 induces chromatin modifications that stimulate transcriptional activation of target genes to regulate entry into the myogenic developmental programme.

/pdf/pax7-activates-myogenic-genes-by-recruitment-of-a-histone-3frnhoeg9i.pdf

Pax7 activates myogenic genes by recruitment of a histone methyltransferase complex

How can we decrease the body’s energy efficiency? The answer to this could be used to fight the exploding obesity crisis. Our ability to accumulate and retain energy reserves once provided a survival advantage. However, these ingrained energy-conservation pathways are now driving unprecedented weight gain in modern societies where calorie-dense food pervades. Burning off excess fuel (analogous to heating a house in winter with the windows open) may be an effective therapeutic avenue to reduce obesity when diet and exercise are not enough. In this week’s Science Express, Vegiopoulos et al. demonstrate that the fatty acid prostaglandin encourages adipocytes (fat cells) to do exactly this—waste energy through increased heat production (1).

In contrast to the familiar white adipocytes that specialize in lipid storage, brown adipocytes burn fat to produce heat (thermogenesis). Infants have prominent depots of brown fat that regulate body temperature. Al-though these “newborn” depots regress during childhood, appreciable amounts of brown fat persist in adults and correlate with adult leanness (2–5). Similarly, brown fat counteracts obesity and metabolic disease in rodents (6) Therefore, enhancing brown fat thermo-genesis is an attractive target for anti-obesity therapy. Vegiopoulos et al. show that white fat can be induced to form intermediate “beige” adipocytes with many of the properties of brown adipocytes, but have a completely independent developmental origin (7) (see the figure).



Figure 1

White to beige. Fat cells can be classified as white storage cells, brown thermogenic cells, or intermediate beige cells. Prostaglandins produced by white fat cells (in response to β3-adrenergic agonists) or from the circulation stimulate the ...



The thermogenic activity of fat tissue is controlled by the sympathetic nervous system. Cold exposure in rodents and humans causes sympathetic nerve fibers to release norepinephrine in fat tissues (6). Norepinephrine then activates β-adrenergic receptors on brown fat cells to stimulate lipolysis and heat production. In white fat depots, prolonged exposure to cold or β3-adrenergic agonists causes tissue transdifferentiation from white to beige (6). Unfortunately, β3-adrenergic agonists have not reached successful clinical application for weight loss because of technical, efficacy and safety issues (8).

Vegiopoulos et al. have now discovered an alternative--prostaglandins drive beige fat development in white fat. This signaling pathway may lead to new therapies for obesity. Specifically, the authors found that white fat cells in mice increase expression of the enzyme cyclooxygenase-2 (COX-2) in response to cold or β3-adrenergic agonists, which consequently produces prostaglandins. Prostaglandins then act locally, triggering brown fat–specific gene expression in white fat cells. In mice engineered to express COX-2 in the skin, a systemic increase of two prostaglandins (PGE2 and PGI2) caused white fat pads to become beige. By contrast, brown fat depots were unresponsive to increased prostaglandin synthesis. Whether housed in cool or warm conditions, the transgenic animals ate more than their wild-type counterparts and remained lean, even when fed a high-fat diet. The lean phenotype was due to elevated energy expenditure and increased body temperature, similar to findings in rats given PGE2 (9). Although many factors suppress beige fat development, prostaglandin is thefirst positive acting signal that is both necessary and sufficient to promote thermogenesis selectively in the white fat compartment.

The relative roles of PGE2 and PGI2 in beige fat development remain to be determined. Genetic deletion of the PGI2 receptor reduces the expression of brown fat-specific genes in subcutaneous but not in visceral fat. Interestingly, the “browning” effect of β3-adrenergic agonists is most prominent in subcutaneous fat. Thus, differential activity of the PGI2 receptor may un-derlie fat depot–selective metabolic effects of β3-adrenergic agonists.

Prostaglandins have a broad array of functions in numerous tissues, with PGE2 acting through four different receptors (EP1-4), and PGI2 acting through the prostacyclin (IP) receptor (10). The complexities of prostaglandin-receptor signaling make therapeutic side effects a concern. For example, prostaglandin powerfully induces the inflammatory response through various combinations of ligand-receptor interactions (11). However, Vegiopoulos et al. did not observe increased systemic inflammation in the transgenic mice that overexpress COX-2. Regardless, unrave-ling the molecular mechanism of prostaglandin action in white fat may reveal more selective methods to promote beige fat development and avoid undesirable and unpredictable side effects. Conceivably, systemic delivery of a highly specific prostag-landin or a synthetic analog could treat obesity

Prostaglandins appear to act directly on fat cells, because treatment of isolated white fat precursors with PGI2 stimulated the expression of brown fat-related genes. PGI2 treatment also amplified this effect in response to norepinephrine. Thus, prostaglandins likely potentiate the response of fat cells to sympathetic nerve activity in tissues. Consistent with this, inhibition of COX-2 suppressed the emergence of beige fat in white fat depots of cold-exposed or β3-adrenergic agonist–treated mice. The intracellular signaling pathways stimulated by norepinephrine involve adenylate cyclase and production of adenosine 3′,5′-monophosphate (cyclic AMP). Prostaglandin receptors also converge on adenylate cyclase (12) and thus may promote the production of beige fat by further activating a common signaling cascade.

The question of where beige cellscome from remains unanswered. The study by Vegiopoulos et al. suggests that progenitor cells are pushed to develop into beige fat by prostaglandins. Alternatively (or additionally), white fat cells could directly convert into beige cells. Regardless of how they arise, the development of beige adipocytes in white fat correlates extremely well with protection against obesity and associated disease. Nonsurgical therapies for obesity are desperately needed. Healthy diet and exercise are accessible and affordable treatments, with broad health benefits beyond weight reduction. However, behavioral modifications are often insufficient. Stimulating white to beige fat conversion through prostaglandin signaling can hopefully be translated into an effective standalone or adjunct therapy to raise energy expenditure and promote weight loss.

/pdf/beige-can-be-slimming-13nqtts6yx.pdf

Beige can be slimming

EBF2 Determines and Maintains Brown Adipocyte Identity

https://www.cell.com/cell-metabolism/pdf/S1550-4131(14)00111-9.pdf

Jeff Ishibashi

Papers

Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice

Pax7 activates myogenic genes by recruitment of a histone methyltransferase complex

Beige can be slimming

EBF2 Determines and Maintains Brown Adipocyte Identity

Prdm16 Is Required for the Maintenance of Brown Adipocyte Identity and Function in Adult Mice