Molecular Mechanisms of Transdifferentiation

Energy expenditure via activation of the orthosympathetic system is essential for the energy balance; indeed, mice lacking all p receptors (1, 2 and 3), though not exhibiting changes in the amount of food intake or in motor activity, become precociously and massively obese [66]. These mice exhibit a complete and early transformation of BAT into WAT, in line with the observations that absence of BAT results in obesity and that ectopic UCP1 expression in WAT makes mice resistant to obesity. These data also agree with the finding that BAT activation and the white-to-brown transdifferentiation induced by administration of p3-AR agonists cure obesity. On the other hand, the mechanism by which mice lacking UCP1 fail to become obese is still obscure.

Since the white-to-brown transdifferentiation induced by the adrenergic stimulus appears to be difficult to harness for human therapeutic goals, recent works indicating possible alternatives to achieve transdifferentiation appear all the more interesting.

Transgenic mice lacking the RIIp subunit (one of the subunits regulating AMPc-dependent pro-teinphosphokinase A, abundant in adipose tissues) overexpress RIa subunit, which involves increased sensitivity of proteinphosphokinase A to AMPc in WAT, and consequent UCP1 gene activation [71]. This entails a brown phenotype of abdominal fat and resistance to obesity.

Foxo2 is a gene for a transcription factor expressed exclusively in adipose tissue. Its overexpression in the adipose tissue of transgenic mice gives rise to an obesity-resistant and more insulinsensitive lean phenotype. These mice show a transformation of white into brown adipocytes [72]. Interestingly, individuals with greater insulin resistance exhibit a reduction of FOXO2 (human foxo2) in subcutaneous abdominal fat accompanied by down-regulation of other genes of the brown adipocytic phenotype.

Expression of protein 4E-BP1, which is essential to regulate post-transcriptional protein synthesis, is high in WAT. In transgenic mice lacking 4E-BP1, brown adipocytes arise in WAT and the adipose organ shrinks in size [73]. This entails that 4E-BP1 protein regulates the post-transcriptional synthesis of some factor involved in the maintenance of the white phenotype in a portion of the adipose organ. The authors suggest that this factor may be PGC1 (peroxisome proliferator-activated receptor-gamma coactivator) - a recently described protein [70] acting as a co-factor of PPARy (see above) in the transcriptional modulation of the adipocyte genome - and that it might be essential to induce transdifferentiation to a brown phenotype [74].

The recent demonstration that white adipocytes from human subcutaneous fat can turn into brown cells via PGC1 transfection [75] lends support to this hypothesis.

A final observation stemming from our collaboration with Kristiansen's group [76] is the demonstration of the important role of protein RB, both during development and in the transdifferentiation induced by the p3-AR agonist CL316,243, in inducing the two phenotypes. In particular, its expression would be responsible for the white phe-notype and its inhibition would trigger white-to-brown transdifferentiation.

Promising metabolic routes to induce transdifferentiation have thus been opened downstream from p-ARs; we hope that they will provide fresh therapeutic options for human obesity and related diseases.

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