Researchers have looked deep into the mouse brain to find out who’s responsible for regained weight.
There’s a brutally simple reason why Ozempic is the new black: dieting is hard and most people put the weight back on.
It’s well established that even when kilos are shed, the body puts hunger into overdrive in a bid to restore the lost weight.
But a study in Cell Metabolism claims to have found a new potential target for preventing weight regain, by examining what happens – in mice – in a brain region called the arcuate nucleus of the hypothalamus when calories are restricted.
The Back Page won’t load you up with too much of the neuroanatomical and neurochemical detail – mainly because we can hear our own synapses frizzling when we try to get our head around it – but the brain cells to meet are the AgRP neurons, which promote hunger in times of calorie scarcity. As the authors write: “AgRP neurons are the ARC neuron population most strongly associated with driving hunger. Caloric deficit, such as during fasting, activates AgRP neurons, which, once engaged, cause voracious feeding and weight gain. Conversely, AgRP neuron inhibition reduces food intake in energy-deprived states, and their ablation leads to starvation and weight loss.”
Another big cell on campus is the thyrotropin-releasing-hormone-expressing paraventricular hypothalamus neuron, or PVHTRH – quite a mouthful, appropriately enough.
The team hypothesised that weight loss would selectively strengthen the synapses that ramp up their activity in lean times.
Using optogenetic tricks on fasting and fully-fed mouse brains, they found fasting doubled the frequency of excitatory post-synaptic currents in the synapses between PVHTRH and AgRP neurons.
They then used chemogenetics to silence PVHTRH neurons in fasting mice, and saw a “profound” reduction in food intake eight and 24 hours after reintroducing food, and a reduction in weight regain over following days.
Silencing PVHTRH neurons prevented the ramping-up of excitatory post-synaptic activity usually seen during fasting, and stimulating PVHTRH neurons did the reverse.
They then looked at the persistence of the effect, observing that mice ate more than usual for four days after one day of fasting, and finding that the increase in synaptic activity continued at least two days afterwards.
When kept on a normal but limited diet for a week after fasting and then allowed to eat ad libitum, the mice exhibited hyperphagia, which was reflected again by persisting brain changes.
The brain changes were reversed, however, upon full restoration of energy deficit.
The best explanation of that data, they conclude, is that “the activity-dependent amplification of synaptic transmission across PVHTRH– > AgRP synapses enhances the effectiveness of this orexigenic pathway over prolonged time periods, which causes, in turn, body weight gain that enduringly persists … Viewed in the context of the emerging obesity epidemic, our results provide new rationales for developing therapeutic strategies to support long-term maintenance of reduced body weight after dieting.”
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