Obesity is the most significant chronic healthcare crisis facing the United States, as well as other countries. Already 1 out of every 3 adults, and 1 out of every 6 children or adolescents, in the U.S. is obese! Leptin is a hormone that has received considerable attention since its discovery in 1994 for its role in regulating metabolism (like a thermostat, or adipostat) and implications for obesity. High leptin levels are associated with feeling satiated and an active metabolism. Though many overweight people have high levels of circulating leptin, it’s been found that their hypothalamic neurons do not receive the signal – a phenomenon known as “leptin resistance.” An animal model that mirrors this is db/db mice, which lack leptin receptors on the surface of they hypothalamic neurons and are therefore morbidly obese (see image).
Reporting in Science this past week, researchers at Harvard Medical School transplanted neurons with the leptin receptor into the hypothalami of db/db mice and as a result were able to partially restore leptin sensitivity and ameliorate their obesity. Two to three months after transplanting 15,000 (a relatively small number) fluorescently-tagged, leptin sensitive neurons into the db/db mice hypothalami, they observed statistically significant drops in blood sugar levels, leptin concentration, and fat mass. In terms of the mechanism and implications, the team concludes:
These results demonstrate that transplanted newborn hypothalamic neurons and progenitors of appropriate developmental stage can chimerically integrate into hypothalamic circuitry as functional neurons with subtype diversity typical of the normal hypothalamus, and that this relatively small number of functionally integrated donor neurons can ameliorate obesity, hyperleptinemia, and hyperglycemia in db/db mice. At least two possible network mechanisms might explain how the relatively few integrated neurons partially rescue the db/db phenotype. Rescue might be solely due to the new neurons themselves. Alternatively, the new, cell-autonomously leptin-responsive neurons might modulate their firing in response to systemic leptin levels, secondarily regulating other neurons in hypothalamic circuitry. Thus, transplanted neurons might act as leptin sensors whose output is then transmitted by endogenous, hypothalamic circuitry still unresponsive to direct leptin activation. Irrespective of the underlying mechanism, these experiments demonstrate that synaptic integration by leptin-responsive donor neurons can impart an organism-level rescue of metabolic defects, thereby providing a proof of concept for cell-mediated repair of a neuronal circuit controlling a complex phenotype.
The senior author, Dr. Jeffrey Macklis, and interviewer stress in the Science Podcast (below) that this is not a feasible therapy for obesity; rather, the value lies in the proof of concept that neuronal circuits may be repaired in this way. This was echoed by co-author and Dean of HMS, Dr. Jeffrey Flier, in an e-mail correspondence:
Shiv Gaglani, Medgadget: How closely does the db/db mouse model mirror obesity etiology in humans? What are the next steps to bring this research to the clinic?
Dr. Jeffrey Flier: The work used the db/db mouse as a facile model system to examine the capacity for cell transplantation to succeed in restoring aspects of a complex circuitry, in this case within hypothalamus. Apart from that, we have absolutely no thought or expectation that neural transplantation would ever be a useful therapy for human obesity. Humans with obesity (apart from a extremely rare subset) do not have the lesion of db/db mice. Even for this rare subset, neural transplantation is not on the horizon. The value of the paper relates to the insights it provides into neural circuitry repair.
When this author corresponded with Dr. Jeffrey Macklis about other diseases or disorders that this research may be relevant to, he responded by sharing the following from the press release:
These findings indicate that the right types of new neurons can functionally integrate anatomically, molecularly, synaptically, electrophysiologically, and with behavioral function to re-wire complex circuitry in the mammalian brain. This supports the idea that precisely controlled maturation of the right types of neurons from progenitors/stem cells might offer new therapeutic approaches for conditions such as ALS, spinal cord injury, Parkinson’s disease, and some forms of epilepsy.
We at Medgadget look forward to reporting on follow-up or related studies!
Paper in Science Transplanted Hypothalamic Neurons Restore Leptin Signaling and Ameliorate Obesity in db/db Mice
Article in Science Now: Transplanted Neurons Curb Obesity
Science Podcast (10 minutes)