Field Notes

Neurons Anticipate Body’s Response to Food and Water

Using leading-edge technology, neuroscientists at Beth Israel Deaconess Medical Center (BIDMC) gained new insight into the brain circuitry that regulates water and food intake. In a new study, the researchers monitored the activity of the neurons that secrete a hormone in response to ingesting food and water. In their study, published online in Neuron, the researchers demonstrated that a subset of neurons starts to prepare the body for an influx of water in the seconds before drinking begins. These neurons help regulate intake by anticipating the effects of drinking from the “top down,” rather than taking cues from the body.

“This study supports the view that when we suddenly detect the availability of food or water, our body starts to prepare itself within seconds for the upcoming bout of eating or drinking,” says co-corresponding author, Mark Andermann, PhD, an assistant professor of medicine in the division of endocrinology, diabetes, and metabolism at BIDMC. “We predict that deficits in this ‘top-down’ control could lead to overshoots in eating or drinking, with many negative consequences.”

Andermann and colleagues, including co-corresponding author Bradford B. Lowell, MD, PhD, a professor of medicine in the division of endocrinology, diabetes, and metabolism at BIDMC, recorded the activity of neurons responsible for releasing the antidiuretic hormone vasopressin in mice. Vasopressin plays a crucial role regulating the body’s relative concentration of water vs salt after eating or drinking, which could otherwise dramatically alter the mix.

“It’s critical to survival that the body has ways to prevent the water concentration outside of cells from changing,” Lowell says. “Anticipating the future consequences of ingesting water helps the body get a head start on managing water balance. The form of rapid, top-down control of this process that we discovered is one important way of managing it.”

In their experiments, Andermann and Lowell watched as the activity of vasopressin-releasing neurons rapidly decreased—within seconds—when water was presented to water-restricted rodents, before they even drank it. In contrast, the sight and smell of food increased the activity in these neurons—again, within seconds—but only following food consumption. That difference in timing suggested that separate neural networks regulate these reactions to water and food.

“This type of rapid regulation wasn’t known to exist and has only been discovered in the last year for hunger neurons and for vasopressin neurons,” Lowell says. “It likely occurs for all forms of homeostatic control. It’s interesting to speculate whether there are individuals out there who have abnormalities in this kind of top-down control.”

“By the same token, we may one day learn that enhancing this top-down control might be a way of regulating meal size without interfering with baseline appetite or with the pleasure of taking the first bite of something delicious,” Andermann says, adding their high-tech methodology will allow them to further investigate the neurons directly “upstream” of the vasopressin neurons. “Because we can now monitor and manipulate the activity of specific sets of neurons, we’re getting closer to being able to directly test these hypotheses and working toward strategies to improve human health.”

— Source: Beth Israel Deaconess Medical Center

 

Fat Stores in Liver Provide Energy During Fasting

In a recent Science Advances article, Mayo Clinic researchers show how hungry human liver cells find energy. This study, done in rat and human liver cells, reports on the role of a small regulatory protein that acts like a beacon to help cells locate lipids and provides new information to support the development of therapies for fatty liver disease.

“Between 30% and 40% of our population have, or are leading toward getting, nonalcoholic fatty liver disease,” says Mark McNiven, PhD, senior author on the paper and director of Mayo Clinic’s Center for Biomedical Discovery. “And that is not including those with alcohol-induced fatty liver; that is also quite prevalent.”

While the mechanisms involved in fat accumulation are the usual targets of research for fatty liver disease, clarifying the cell’s mechanism for breaking down fat also could provide valuable information to fuel the discovery of breakthrough treatments in the future.

Fueling the Hungry Cell
In a well-fed cell, fat deposits, called lipid droplets, are nutritional insurance. They’re ignored by the cell as it fuels growth and division via its normal pathway. But, in a starving cell, the normal pathway switches off, and a recycling process, called autophagy, switches on. Autophagy is a way for cells to break down macromolecules, such as protein and fat, into their component parts to be used in cell processes.

Under starvation conditions, the cell’s recycling pathway directs specialized vessels to engulf lipid droplets. These vessels, called autophagosomes, then link with another organelle, called a lysosome, which is filled with acidic enzymes. When these two merge, the resulting structure is called an autolysosome. Within the autolysosome, the enzymes break apart the fat droplet free fatty acids.

How Does a Hungry Cell Find the Fat? It Follows the Beacon
Zhipeng Li, first author and a student at Mayo Clinic Graduate School of Biomedical Sciences, noticed that, within the hungry cells, one protein, called Rab10, was intimately associated with many of the lipid droplets. Rab proteins operate like switches; when bound to a substance, they switch on and facilitate interactions in the cell. There are more than 60 different Rab switches, or small regulatory GTPases, in the human genome.

“In this paper, we show that, when Rab10 is switched on, it will bind to a lipid droplet and cause the autophagosome to dock on the droplet surface, recruit other proteins, and digest the lipid into a free fatty acid energy source,” Li says.

McNiven explains that cells have sensors that detect low energy levels and respond.

“Rab10 switches on and builds up around the lipid droplet,” McNiven says. “Then, the cell activates its lysosomes that then target these lipid droplets and go after them. So this was an important step that we provided between the sensing mechanism of starvation and how that is signaling to this switch to go after lipid droplets.”

— Source: Mayo Clinic