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Neuronal transplants for treatment of obesity

The views expressed are those of the author and are not necessarily those of Scientific American.


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There are many different factors which go into whether animals (or humans) develop obesity and diabetes. Different sensitivity to different chemicals, in different areas of the body and brain, can cause major differences in feeding behavior, body weight, fat, and insulin sensitivity. And now we’ve learned that changes in one circuit of the hypothalamus could make a big difference in a certain kind of obesity in mice.


(Source)

Czupryn et al. “Transplanted Hypothalamic Neurons Restore Leptin Signaling and Ameliorate Obesity in db/db Mice” Science, 2011.

We’ll start with the db/db mouse, pictured above (on the left). This mouse is genetically designed to develop severe morbid obesity and diabetes soon after birth. This is because it lacks a receptor for a hormone called leptin. Leptin is a hormone that plays a major role in appetite and metabolism. Decreasing your sensitivity to leptin, by decreasing leptin receptors, say (as in the the db/db mouse), produces striking obesity and type 2 diabetes in humans and mice. Increasing your sensitivity to leptin, by, say, increasing your leptin receptors, can rescue this, resulting in lower body weight and more sensitivity to insulin.

But these are global changes, throughout the body. The question is, where in the body do these leptin receptor changes really make a difference? Recent papers have suggested that the hypothalamus could play a major role. The hypothalamus, an area of your brain right above your pituitary gland, is a big connection between the brain and the endocrine system, an area where sensitivity to hormones could have a major impact on behavior and body regulation. And the hypothalamus regulates things like sleep, thirst, body temperature, and hunger.


(Source)

The authors of this study wanted to see HOW increasing leptin-receptor containing neurons in the hypothalamus could work to help db/db mice. They took newborn db/db mice and controls, and gave them an implant of neurons containing, not just the leptin receptor, but a fluorescent protein to they could track their growth and position.

After the mice grew up, the authors looked to see where the neurons went, and what they did when they got there. They found that the neurons were able to integrate into the circuitry of the hypothalamus, expressing the leptin receptor, and forming synapses with local cells. The new neurons responded not only to leptin signals, but also to signals from glucose and insulin, an important step in how leptin sensitive cells can regulate insulin sensitivity.

But new neurons that glow are no good unless they have function. As it happens, these did.

You can see that the mice treated with the leptin expressing neurons (shown in green) had a lower bodyweight than their non-neuron transplanted counterparts (in red and blue), but not as low a weight as control mice that were not db/db mice (in pink and gold). The story was similar for other measures.

The chimeric (in green) had lower fat mass, leptin, and blood glucose than his db/db controls, but it never got as low as the controls that were not db/db. This shows that, while leptin receptors in the hypothalamus can regulate some aspects of body weight and blood glucose in these mice, other areas must be important as well to create a mouse with normal body weight and blood glucose.

Still, though it’s not the whole answer, it’s an interesting start to understanding not only the role of the hypothalamus in obesity and type 2 diabetes, but also how we might be able to change receptors in the brain to restore leptin sensitivity, and decrease sever obesity and the type 2 diabetes that often goes with it.

Czupryn, A., Zhou, Y., Chen, X., McNay, D., Anderson, M., Flier, J., & Macklis, J. (2011). Transplanted Hypothalamic Neurons Restore Leptin Signaling and Ameliorate Obesity in db/db Mice Science, 334 (6059), 1133-1137 DOI: 10.1126/science.1209870

Scicurious About the Author: Scicurious is a PhD in Physiology, and is currently a postdoc in biomedical research. She loves the brain. And so should you. Follow on Twitter @Scicurious.

The views expressed are those of the author and are not necessarily those of Scientific American.





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