"Nature" sub-journal: Professor Li Bo's team in Cold Spring Port Laboratory found a neural pathway that "can't control the mouth"

*For medical professionals only

According to the World Health Organization, the number of obese people in the world is as high as 1 billion, and this number is gradually rising
.
In addition to genetic and drug factors, most of the causes of obesity can be summarized as "can't control the mouth, can't open the legs", today we will talk about "can't control the mouth" this matter
.

Feeding behavior can be divided into two categories: steady-state feeding and hedonic feeding
.
Simply put, eating hungry is steady-state feeding; And after eating, because of hunger, it is hedonic feeding [1].

This kind of eating to satisfy emotions is easy to induce overeating, which in turn causes metabolic diseases
such as obesity, diabetes and hyperlipidemia.

The neuroregulatory mechanisms of homeostatic feeding have been extensively studied [2], but the neural circuits that regulate hedonic feeding are still unclear
.

Studies have shown that the amygdala is highly correlated with driving overeating [3].

The amygdala is the subcortical center of the limbic system of the brain, which has the function
of producing emotions, increasing memory, and regulating visceral activity.

Recently, Professor Li Bo's team of Cold Spring Harbor Laboratory in the United States published a study on neurons in the amygdala driving hedonic eating in the journal Nature Neuroscience [4], revealing that IPAC-NTS neurons in the amygdala are key nodes in promoting hedonic eating and energy metabolism, which is expected to provide new treatment strategies
for the prevention and treatment of obesity.

Screenshot of the first page of the paper

Neurotensin (Nts) directly promotes fat absorption and induces obesity [5].

Through single-molecule fluorescence in situ hybridization experiments, the researchers showed that neurotensin enrichment was expressed in the anterior and hindlimb interstitial nuclei (IPAC) regions of the mouse amygdala (hereinafter referred to as IPAC-Nts neurons).

In the experiment, the researchers provided mice with common or high-fat food and labeled activated neurons
in IPAC with immunofluorescent c-Fos.
The results showed that although the intake of both foods was consistent in mice, only intake of high-fat food (HFD) activated mouse IPAC-Nts neurons (Figure 1A-B).

Based on this, they speculate that the main factor that activates IPAC-NTS neurons is the intake of fatty foods, rather than energy deprivation or ordinary eating behavior
.

To test this hypothesis, the researchers employed fiber optic calcium imaging to measure the response of IPAC-NTS neurons when mice ingest regular or fatty foods (Figure 1C).

The results showed that not only the amplitude of Nts neurons caused by high-fat food in the starved state was much higher than that of ordinary food (Figure 1D), but also high-fat food in the full state could activate IPAC-Nts neurons (Figure 1E).

Based on this, they confirmed that high-fat foods can activate IPAC-Nts neurons
.

Figure 1.
Mice ingesting high-fat foods activates their IPAC-Nts neurons

As the most important factor in regulating food preference and intake, is the taste of food related to the activation of IPAC-Nts neurons?

The researchers found that both ingestion of liquid fat or sucrose in mice activated IPAC-Nts neurons (Figure 2A-B).

Conversely, quinine with a bitter taste inhibits neuronal activation (Figure 2C).

Further, they found a strong correlation between the amplitude of neural responses elicited by food taste and food preference (Figure 2D).

These results suggest that the activity of IPAC-Nts neurons at feeding represents the deliciousness of the food and the preference of mice for that food
.

Figure 2.
The degree of activation of IPAC-NTS neurons represents the mice's preference for food choices

Not even a taste, just smell affects the state of neurons, and the researchers gave mice three different odors and examined the responses of Nts neurons (Figure 3A): HFD (high-fat food solution), BA (rotten food solution), and MO (pure solubilizer).

The results showed that HFD can activate IPAC-Nts neurons, but BA and MO odors cannot activate this neuron (Figure 3B).

To further clarify whether IPAC-Nts neurons reflect more subtle dietary preferences, the researchers gave mice four different odors: HFD^CO (coconut flavored high-fat food solution), HFD^OO (olive oil-flavored high-fat food solution), Chow (common food solution), and MO (pure dissolver).

When mice were hungry or satieated, IPAC-Nts neurons responded more to the taste of both classes of fatty foods than to regular foods (Figures 3C and 3D).

Even when the mice were full, the mice's favorite HFD^CO could still activate IPAC-Nts neurons
.
The above data suggest that hedonic eating activates IPAC-Nts neurons
.

Figure 3.
Odors can activate IPAC-Nts neurons

The researchers speculate that IPAC-NTS neuronal activation may also backstimulate hedonic eating
.
To test this hypothesis, they used optogenetic techniques to attach "switches" to mouse IPAC-Nts neurons (Figure 4A).

After the IPAC-Nts neurons were activated, the mice that consumed both ordinary and fatty foods increased their intake, but the latter increased much more (Figure 4B), while after temporary or long-term inhibition of IPAC-Nts neurons, their feeding behavior was inhibited
regardless of whether the mice were hungry or full.

Figure 4.
Activation of IPAC-Nts neurons promotes hedonic eating

IPAC-Nts neuronal inactivation not only hinders eating in mice, but also increases oxygen intake and reduces the respiratory exchange ratio, thereby enhancing the oxidation rate of lipids (Figure 5A).

In addition, long-term inhibition of IPAC neurons significantly reduced mouse body weight (Figure 5B) and blood glucose levels (Figure 5C), and also reduced the amount of lipid droplets in brown fat (Figure 5D).

Therefore, IPAC-NTS neuronal inactivation enhances energy expenditure and, in the long term, contributes to weight loss and healthy energy metabolism
.

Figure 5.
IPAC-NTS neuronal inactivation promotes energy metabolism and enables weight loss

In order to explore the signaling of IPAC-Nts neurons and further explain how this neuron is interrelated with the feeding system, the researchers used monosynaptic retrograde rabies virus to track upstream signals, and found that IPAC-Nts neurons receive projected signals from multiple brain regions, including the striated bed nucleus, nucleus accumbens, paraventricular nucleus, nodular nucleus, paraventricular nucleus, etc
.

In addition, they used the GFP fluorescent virus to identify downstream targets of IPAC-nts neurons and found that the neuron can project to multiple regions, including the lateral hypothalamus (LHA).

LHA is a highly heterogeneous region involved in regulating physiological functions such as energy intake, energy metabolism, food preference, and autonomous function [6].

In order to clarify the role of LHA in IPAC-NTS in energy metabolism, the researchers injected cholera virin into mouse LHA and reverse-tracked it, and found that IPAC-NTS neurons projected to LHA, and simple activation of LHA neurons could also drive mice to consume more high-fat foods than ordinary foods
.
In other words, activating LHA neurons can also drive hedonic eating, a phenomenon consistent with
the activation of IPAC-NTS neurons.

Through a large number of experiments, the researchers have provided new insights into the amygdala IPAC-Nts neurons driving hedonistic eating, revealing that IPAC-NTS neurons receive sensory stimulation signals and project to LHA, which in turn causes feeding behavior
.
This study provides important clues for the regulatory mechanism of overeating, which is expected to provide a new scientific basis
for the prevention and treatment of obesity.

References

[1]   Ziauddeen H, Alonso-Alonso M, Hill J O, et al.
Obesity and the neurocognitive basis of food reward and the control of intake[J].
Advances in Nutrition (Bethesda, Md.
), 2015, 6(4): 474–486.

[2]   Rossi M A, Stuber G D.
Overlapping Brain Circuits for Homeostatic and Hedonic Feeding[J].
Cell Metabolism, 2018, 27(1): 42–56.

[3]   Jennings J H, Rizzi G, Stamatakis A M, et al.
The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding[J].
Science (New York, N.
Y.
), 2013, 341(6153): 1517–1521.

[4]   Furlan A, Corona A, Boyle S, et al.
Neurotensin neurons in the extended amygdala control dietary choice and energy homeostasis[J].
Nature Neuroscience, 2022.

[5]   J L, J S, Yy Z, et al.
An obligatory role for neurotensin in high-fat-diet-induced obesity[J].
Nature, Nature, 2016, 533(7603).

[6]   Berthoud H-R, Münzberg H.
The lateral hypothalamus as integrator of metabolic and environmental needs: from electrical self-stimulation to opto-genetics[J].
Physiology & Behavior, 2011, 104(1): 29–39.

Responsible editorYing Yuyan