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From body to brain and back again—how the hormone leptin utilizes brain cell circuits to regulate appetite, calorie burning, and glucose levels

Scientists have used a new genetic tool in mice to map out the cellular brain circuits used by the hormone leptin to control energy balance (calories consumed versus calories burned) and blood glucose (sugar) levels. Leptin, which is produced in fat tissue, acts in the brain to regulate food intake, promote calorie-burning, and control blood glucose (sugar) levels following a meal. Leptin deficiency or dysfunction of leptin receptors (molecules on the cell surface with which leptin interacts) results in severe obesity and diabetes in humans. It has been widely suggested that certain types of brain cells called “AGRP” and “POMC” cells, which contain leptin receptors, are essential to carrying out leptin’s effects. However, selectively deleting leptin receptors in these cells in mice using traditional genetic manipulation methods has failed to reproduce the obesity and diabetes seen in mice completely lacking leptin receptors, suggesting that other cells may play a key role.

To identify leptin’s primary target, researchers used a chemical agent to induce diabetes in male mice, which subsequently leads to leptin deficiency. They then determined the brain region primarily affected by the loss of leptin by measuring brain activity: during leptin deficiency, one brain region became intensely active and when they administered leptin, the activity subsided. This finding led the researchers to investigate if this area contained AGRP cells because it is known that leptin suppresses AGRP cell activity. After administering an agent that selectively suppresses AGRP cell activity in diabetic, leptin-deficient mice, the mice experienced significantly reduced blood glucose levels, indicating that AGRP cells play a primary role in leptin responsiveness and blood glucose control. But, why had previous studies deleting leptin receptors in AGRP cells failed to induce diabetes in mice? The answer could lie in the limitations of older, traditional methods.

To explore this further, the researchers used a powerful, new genetic engineering tool—one that had not been used in the previous studies—to selectively delete leptin receptors in AGRP cells of non-diabetic male and female mice. This deletion induced severe obesity and diabetes, increased food intake, and reduced calorie burning. These results suggest that leptin is acting through its receptors on the surface of AGRP cells to induce widespread metabolic consequences. Interestingly, when they performed a similar experiment by selectively deleting leptin receptors in POMC cells, they observed no effect on body weight or blood glucose, indicating that leptin acts primarily on AGRP cells to maintain blood glucose control and prevent weight gain and diabetes. They further investigated the mechanism by which leptin suppresses activity of AGRP cells and found that by acting through its receptor, leptin modifies the function of nearby proteins on the surface of AGRP cells to reduce the cells’ activity and modulate communication between cells.

Taken together, these findings identify the critical elements of a brain cell circuit through which leptin governs energy balance and blood glucose levels. Importantly, this study shines a light on the disparity in experimental results that can occur when different gene-altering methodologies are used and suggests a critical need to reexamine previous conclusions drawn from past studies.

References

Xu J, Bartolome CL, Low CS,…Kong D. Genetic identification of leptin neural circuits in energy and glucose homeostases. Nature. 556: 505-509, doi: 10.1038/s41586-018-0049-7, 2018.

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