Mol Cell Endocrinol. 2021 May 1;527:111218. doi: 10.1016/j.mce.2021.111218. PMID: 33636254
This study used a high fat and high sucrose diet to generate obese mice. The offspring of these mice showed activation of the unfolding protein response and the heat-shock response in the hypothalamus as early as weaning. This was associated with malformed paraventricular nucleus axonal projections and defective leptin signaling. Intriguingly early inhibition of hypothalamic ER stress in the offspring failed to improve the metabolic outcome but worsened it. A key molecule (called heat shock protein 70 (HSP70)) was altered in the early postnatal developing hypothalamus which might lead to permanent unfolded protein response activation later in life.
Maternal overnutrition and obesity are risk factors for later development of childhood obesity and type 2 diabetes mellitus. The underlying mechanisms involved in the development of childhood obesity following maternal obesity are unknown but might involve changes in the feeding center of the hypothalamus. In the hypothalamus, there are two key neuronal subtypes (anorexigenic and orexigenic) which impinge on the paraventricular nucleus which regulates feeding behavior. Leptin plays a key role in regulating this whole circuit. In mice models of obesity, endoplasmic recticulum (ER) stress is noted in the hypothalamus early in the neonatal period with defective changes in the paraventricular neuronal projections. ER stress is controlled by the unfolding protein response and the heat-shock response which is a cellular protective mechanism activated by different stressors where chaperon proteins prevent cellular stress response by protein folding and re-folding and by activating autophagy.
These observations suggest that developmental exposure to a maternal obesogenic environment may lead to an imbalance in the unfolded protein and heat shock responses in the postnatal developing hypothalamus. This imbalance might lead to defects in obesity programming of the offspring.