FIGURE 9.

Model for hypothalamic defect of autophagy in the pathogenesis of obesity and related disease. Chronic obesogenic conditions (including caloric excess and possibly aging) can reduce the function of hypothalamic autophagy, leading to IKKβ/NF-κB activation and inflammation in the hypothalamus. As a result, the hypothalamic function of regulating body weight and metabolic homeostasis is impaired, which potentiates the development of obesity and related metabolic diseases. In conjunction with the literature, oxidative stress and ER stress are likely involved in causing hypothalamic defect of autophagy, and, on the other hand, the onset of defective hypothalamic autophagy is predicted to also promote these intracellular stresses. In sum, all these changes can sustain IKKβ/NF-κB activation and related inflammation in the hypothalamus and thereby exacerbate the progression of obesity and related metabolic disease.