While we all know that eating fatty food pushes up our body weight, a new study now shows it also affects the way the brain keeps track of and corrects all metabolic irregularities in the body. Soon after tucking into a high-fat, high-carb meal – as soon as three days later – the hypothalamus shows inflammation.
High-fat diets contribute to irregularities in the hypothalamus region of the brain, which regulates body weight homeostasis and metabolism. Image Credit: Wanchai / Shutterstock
The hypothalamus is the symphony conductor of the body, a small but vital region of the brain where a lot of things come together to regulate the smooth functioning of the human organism. This early change in the health of the hypothalamus, preceding even the first outward signs of obesity, happens very fast indeed, and motivated the current research into the cell-level changes that were occurring.
The results were striking: the microglia of the brain, which are the primary immune mechanism against foreign intruders to the central nervous system, were being activated on a high-fat diet. This in turn was due to mitochondrial shifts. The mitochondria are microscopic bean-shaped organelles or tiny organ-like structures within individual cells. They drive the whole energy processing unit of the cell, breaking down sugars atom by atom to extract chemical energy from the reaction and store it for future use in all bodily processes.
However, the mitochondria in the microglia apparently shrink and begin to function differently because of a protein called uncoupling protein 2 (UCP2). Originally discovered in brown fat, which is a special type of body fat that yields more heat than white fat, UCP2 is synthesized within the hypothalamic microglia in response to a high-fat diet. Other things which promote UCP2 synthesis include thyroid hormones, catecholamine hormones like adrenaline and noradrenaline, and retinoids.
In animals on a high-fat diet, UCP2 is activated by fatty acids. This protein uncouples or unlinks the extraction of energy from food from the mitochondrial chemical conveyor belt that stores this energy in the form of ATP. In the current experiment, increased UCP2 levels cause increased ATP production and increased mitochondrial respiration.
As a result of microglial activation by UCP, certain neurons in the hypothalamus act to increase the animals on a high-fat diet to eat more and to gain weight. When the UCP2 gene was knocked out, however, animals on the same diet ate significantly less, used up more energy, and did not put on weight. Along with this, the synapses bringing in information to the hypothalamic neurons showed a rearrangement, while other neurons in the POMC area of the hypothalamus that reduce the appetite are activated. An associated change was a decreased sensitivity to leptin, which in turn promotes obesity.
Scientists think this might have been an adaptation to earlier conditions of food scarcity, allowing the animal to eat well and store up fat when fatty food was available. However, this UCP2-mediated mechanism becomes counterproductive in a situation of having constant access to high-fat food, causing microglial activation and diet-induced obesity.
Researcher Sabrino Diano wants to understand what makes people eat more or less. The current research also drives questions as to the effect of microglial activation on various neurologic diseases like Alzheimer’s disease, which is more common among obese people.
The study was published in the journal Cell Metabolism on September 5, 2019.
Microglial UCP2 Mediates Inflammation and Obesity Induced by High-Fat Feeding, Jung Dae Kim, Nal Ae Yoon, Sungho Jin, Sabrina Diano, Cell Metabolism, DOI: https://doi.org/10.1016/j.cmet.2019.08.010