The obesity epidemic in the face of homeostatic body weight regulation: What went wrong and how can it be fixed?

Ever since the pioneering discoveries in the mid nineteen hundreds, the hypothalamus was recognized as a crucial component of the neural system controlling appetite and energy balance. The new wave of neuron-specific research tools has confirmed this key role of the hypothalamus and has delineated many other brain areas to be part of an expanded neural system sub serving these crucial functions. However, despite significant progress in defining this complex neural circuitry, many questions remain. One of the key questions is why the sophisticated body weight regulatory system is unable to prevent the rampant obesity epidemic we are experiencing. Why are pathologically obese body weight levels defended, and what can we do about it? Here we try to find answers to these questions by 1) reminding the reader that the neural controls of ingestive behavior have evolved in a demanding, restrictive environment and encompass much of the brain's major functions, far beyond the hypothalamus and brainstem, 2) hypothesizing that the current obesogenic environment impinges mainly on a critical pathway linking hypothalamic areas with the motivational and reward systems to produce uncompensated hyperphagia, and 3) proposing adequate strategies for prevention and treatment.