Abstract
Neurons expressing agouti-related protein (AgRP) are essential for feeding. The majority of these neurons are located outside the blood-brain barrier (BBB), allowing them to directly sense circulating metabolic factors. Here, we show that, in adult mice, AgRP neuronsoutside the BBB (AgRPOBBB) were rapidly ablatedby peripheral administration of monosodium glutamate (MSG), whereas AgRP neurons inside the BBB and most proopiomelanocortin (POMC) neurons were spared. MSG treatment induced proliferation of tanycytes, the putative hypothalamic neural progenitor cells, but the newly proliferated tanycytes did not become neurons. Intriguingly, AgRPOBBB neuronal number increased within a week after MSG treatment, and newly emerging AgRP neurons were derived from post-mitotic cells, including some from the Pomc-expressing cell lineage. Our study reveals that the lack of protection by the BBB renders AgRPOBBB vulnerable to lesioning by circulating toxins but that the rapid re-emergence of AgRPOBBB is part of a reparative processto maintain energy balance.
Highlights
The ability to monitor the body’s energy stores and adjust appetite and energy expenditure is essential for survival in an environment where food availability is unpredictable
We have recently shown that 60%–70% of agouti-related protein (AgRP) neurons in adult mice are located outside the blood-brain barrier (BBB) (AgRPOBBB), while most of the neighboring proopiomelanocortin (POMC) neurons are inside of the BBB (Olofsson et al, 2013)
We investigated whether AgRP neurons, the majority of which are not protected by the BBB, may undergo basal turnover
Summary
The ability to monitor the body’s energy stores and adjust appetite and energy expenditure is essential for survival in an environment where food availability is unpredictable. Neurons expressing agouti-related protein (AgRP) are unique among hypothalamic neurons due to their anatomical relationship with the blood-brain barrier (BBB). We have recently shown that 60%–70% of AgRP neurons in adult mice are located outside the BBB (AgRPOBBB), while most of the neighboring proopiomelanocortin (POMC) neurons are inside of the BBB (Olofsson et al, 2013). AgRPOBBB are in a position to directly sense dynamic changes in circulating leptin levels, whereas hypothalamic neurons behind the BBB are less sensitive to these changes, making AgRPOBBB first-line responders to dynamic changes in nutritional status (Olofsson et al, 2013). AgRP neurons are indispensable for appetite regulation and lesioning of these neurons could have severe metabolic consequences
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