Adipogenesis is promoted by an elevated adiponectin level

Nutritional environment and conditions experienced by the embryo in utero shape the susceptibility to disease and metabolism throughout the later life. Embryonic cells are both, sensitive to nutritional and hormonal changes, and flexible with high adaptive plasticity for survival and differentiation. A maternal type 1 or insulin-dependent diabetes mellitus (IDDM) leads to an increased expression of adiponectin in the rabbit blastocysts as part of a molecular adaptation. Adiponectin has various functions in lipid and carbohydrate metabolism and is therefore essential for energy homeostasis. Altered adiponectin levels have been epidemiologically associated with obesity and insulin resistance.

To evaluate the effects of an increased adiponectin level for determination and differentiation of embryonic cells, we used the pluripotent murine embryonic stem cell (ESC) line CGR8 as a model of adipogenesis in vitro. An early treatment of the CGR8 cells with retinoic acid and subsequent culture with insulin and triiodthyronine results in functional adipocytes within 21d. CGR8 cells encompass the full process of adipogenesis thus offering a suitable model to study the initial stages of adipocyte determination and differentiation. Adipogenic differentiation efficiency was analyzed by fluorescence-activated cell sorting.

An early short-time adiponectin exposure (1µg/ml) to undifferentiated cells increased the amount of terminal differentiated adipocytes by 260%, demonstrating a direct influence of adiponectin on adipogenesis in CGR8 cells. The molecular pathway implied a key role of the transcription factor cAMP responsive element binding protein (CREB). CREB promotes adipogenesis and regulates the transcription of adipocytes specific genes including PPARg2, CEBPb, FAS and FABP. In adiponectin stimulated ESC the CREB phosphorylation was induced, indicating that an early CREB activation correlates with forced adipogenesis. The stimulatory role of adiponectin on CREB was confirmed in rabbit blastocysts.

Our work shows that early changes in adiponectin due to maternal disorders as diabetes mellitus give rise to an accelerated adipogenesis in later life.