Adipocyte ALK7 links nutrient overload to catecholamine resistance in obesity

摘要

Adrenaline and noradrenaline are two hormones that trigger the burst of energy and increase in heart rate and blood pressure that are needed for the ‘fight-or-flight’ response. Both belong to a group of chemicals called catecholamines. These chemicals bind to cells carrying proteins called adrenoceptors on their surface and stimulate the breakdown of fat, which releases energy. However, when nutrients are plentiful, fat cells become resistant to catecholamines and instead store fat so it can be used for energy if food becomes scarce. In the industrialized world where food is easily and constantly accessible, this resistance can cause an unhealthy increase in body fat and result in obesity. Increasing fat metabolism by making fat cells more able to respond to catecholamines is an attractive strategy for combating obesity. Indeed, drugs that mimic the effect of catecholamines on an adrenoceptor found in mice reduce obesity caused by over-eating. However, these drugs are ineffective in humans and can cause harmful side effects to the cardiovascular system, including high blood pressure and an increased heart rate. Devising a strategy that specifically targets catecholamine resistance in fat cells is therefore desirable. A protein called ALK7 is a cell surface receptor that is predominantly found in fat cells and tissues involved in controlling the metabolism. Mice with a mutation in ALK7 that stops this protein from working properly accumulate less fat than mice with a functional version of the protein, but it is not known why. To understand ALK7's involvement in fat metabolism, Guo et al. created mice whose fat cells lack ALK7, but whose other cells all produce ALK7 as normal. When fed a diet rich in fat, these mice are leaner than regular mice and they burn more energy. The metabolic responses seen in ALK7 mutant mice are very similar to those seen in mice treated with drugs targeting adrenoceptors, suggesting that there may be a link between ALK7 and catecholamine resistance. Indeed, Guo et al. demonstrate that fat cells lacking ALK7 have an increased sensitivity to catecholamines when the mice are on a high fat diet, which decreases the amount of fat the mice accumulate. Conversely, increasing the activity of ALK7 reduces the ability of the cells to respond to catecholamines, and they accumulate more fat. Guo et al. also generated a second line of mice carrying a mutation in ALK7 that does not affect its function, but renders it sensitive to inhibition by a custom-made chemical. When these animals were on a high-fat diet, administering the chemical made the mice leaner, suggesting that inhibiting the ALK7 receptor can prevent obesity in adult animals. Guo et al. also performed experiments in human fat cells, which showed that the ALK7 receptor works in a similar way in human cells as it does in mice. As ALK7 is largely specific for fat cells and is not known to affect the cardiovascular system, drugs that inhibit ALK7 could potentially safely suppress catecholamine resistance and reduce human obesity.