Figure 1.

Schematic presentation of the energy balance paradigm. (a) Body weight follows the difference between EI (energy_in) and EE (energy_out). With increasing body weight energy_out increases. By contrast, reducing body weight decreases energy_out. Vice versa there are no effects of increases in energy_out by strenuous exercise on body weight. An increase in body weight does not automatically result in a compensatory decrease in energy_in. Body weight-independent feedback controls between energy_out and energy_in had been proposed but have only been shown for underfeeding. (b) Pharmacological inhibition of the sodium-glucose co-transporter 2 (SGLT2) results in glucosuria of about 90 g/day. To test the energy balance paradigm the effects of SGLT2-inhibition on energy_in and energy_out has to be tested. (c) SGLT2-inhibition resulted in an increase in energy_in with no changes in energy_out. However, an unchanged EE the increase in energy_in does not match urinary energy losses resulting in a negative energy balance. See Ferrannani et al. 43 and text for further details.