Dose-related steady states of fat loss in long-term leptin-treated ob/ob mice: leptin resistance or desensitization versus counterregulatory signaling.

We tried to unravel why leptin's fat store depleting action levels off in the course of long-term applications. Supplying leptin by minipump infusion for 2 months to ob/ob mice at rates between 115 pmol day(-1) and 460 pmol day(-1) resulted in stable plasma leptin levels between 0.2 ng ml(-1) and 8 ng ml(-1). Initial treatment effects were leptin dose-dependent reductions in food intake and body mass, especially in fat content, followed by re-increases of food intake to levels only 4-18% below pre-treatment levels. Decreased body mass subsequently stabilized dose-dependently with body fat contents between 4% and 33% showing that total fat depletion was not a precondition for the progressive reduction of leptin-induced anorexia. Oxygen consumption measurements excluded contributions of enhanced energy dissipation to fat depletion. Plasma insulin concentrations declined from excessively high pre-treatment levels to steady, leptin dose-dependent levels within the normal range. Temporary anorexia in response to repeated additional 1-day leptin injections (100 pmol g(-1) day(-1)) remained unchanged throughout long-term leptin infusion. Among various alternatives considered to explain the adipostatic equilibrium attained at new, dose-dependent levels under long-term leptin treatment, interaction between the leptin signal and at least one counteracting signal increasing with fat depletion is proposed as the most plausible working hypothesis.