Cells "respond" to stress by creating more protective molecules that counteract this stress. Among other things, these ensure that protein maturation is fast, precise and – as far as possible – error-free. Thus, the body adapts to extreme conditions that can arise if we constantly eat too much or too little. "Usually the term “stress” is associated with something negative. However, the cellular stress response is a process that ensures that the cells remain healthy – something positive in this context," said Dr. André Kleinridders, who is investigating the causes and consequences of insulin resistance in the brain at the German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) and the German Center for Diabetes Research (DZD). Insulin is responsible for the fine tuning of brain function in the central nervous system. It influences the reward center, food intake, cognition and behavior. Insulin resistance means that the hormone is no longer effective even though it is available in sufficient quantities.
Kleinridders and his team have now discovered that insulin in the brain causes the cell to produce more protective molecules, including the heat-shock proteins HSP10 and HSP60, which are indispensable for the assembly of proteins. Via this signaling pathway, insulin controls mitochondrial function in the hypothalamus – the brain region that regulates our eating behavior. The vital energy for the body is produced in these organelles of cellular respiration. This is why the mitochondria are referred to as the “power plants” of the cells. A defective stress response would result in mitochondrial dysfunction and thus lead to neuronal cell death. The loss of these molecules can be associated with both metabolic diseases such as type 2 diabetes and various neurodegenerative diseases.
More "stress", less hunger
Researchers already knew that intranasal insulin reduces hunger for high-sugar food in healthy people. When insulin is administered through the nose, for example with a spray, it bypasses the blood-brain barrier and reaches the brain directly. In the current study, researchers observed that healthy mice that "snuffed" insulin likewise ate less of the tasty chow on offer, but which in this experiment was not high in sugar, but rather a high-fat diet. The team of scientists also found that the mice increasingly formed the protective molecules mentioned above, which support the function of the mitochondria in the hypothalamus and thus neuronal health.
The research team also investigated diabetic mice that did not have endogenous insulin and mice that became resistant to the hormone due to high-fat foods. Both groups had a reduced stress response. By stimulating with insulin, the response could be normalized again. "We still do not know why diabetic patients are at an increased risk of developing Alzheimer's or Parkinson's. The insulin-dependent regulatory mechanism of the stress response provides important explanatory approaches that definitely should be pursued," said Kristina Wardelmann, doctoral student in the Junior research Group and first author of the study.
Sustainable promotion of healthy aging
In addition to insulin, dietary components such as fat also seem to influence the stress response in the brain. "Presumably, the brain perceives increased levels of fatty acids and activates adaptive metabolic responses," said Kleinridders. In the future, the group also wants to look for nutrients that have a similar positive effect as insulin on the function of the mitochondria and thus on the energy supply and metabolism. This knowledge could help to develop novel intervention strategies that sustainably promote healthy aging.
Wardelmann K, Blümel S, Rath M, Alfine E, Chudoba C, Schell M1, Cai W, Hauffe 1, Warnke K, Flore T, Ritter K, Weiß J, Kahn CR, Kleinridders A. Insulin action in the brain regulates mitochondrial stress responses and reduces diet-induced weight gain. Molecular Metabolism (2019)