Negative Feedback Control of Hypothalamic Feeding Circuits by the Taste of Food

Neurology Basic Medical Sciences Life Sciences Medicine Biochemistry
hypothalamus taste negative feedback AGRP neurons hunger control

I. Research Background

The taste of food has a significant impact on the feeding motivation of animals. Previous research has shown that taste, as a positive feedback signal, can enhance the feeding motivation of animals. However, in recent years, studies on whether taste also plays a role in suppressing feeding and helping achieve negative feedback control of eating have been increasing. The perception speed of nutrients in the gut is relatively slow, while the stimulus from taste is immediate, suggesting that taste may play a regulatory role in the termination of feeding. In human studies, the act of oral chewing has been shown to enhance satiety more than food delivered directly through the gastrointestinal tract, further supporting the negative feedback role of taste during feeding. However, how taste functions in the termination of feeding at the neural mechanism level remains a mystery.

II. Research Source

This study was conducted by Tara J. Aitken, Zhengya Liu, Chris Barnes, and Zachary A. Knight from the University of California, San Francisco, and was published in the journal “Neuron”. The study used techniques such as neural optogenetics and fiber photometry to deeply explore the effects of food taste on the activity of agouti-related peptide (AGRP) neurons in the hypothalamus, revealing the dynamic regulatory role of taste signals on the feeding process.

III. Research Methods

1. Experimental Procedure Design

The study first recorded the dynamic activity of AGRP neurons during feeding. The experiment used optogenetic techniques on mice to manipulate and record changes in AGRP neuron activity during feeding. Additionally, the study employed “closed-loop optogenetic stimulation” to reverse taste-induced inhibition of AGRP neurons in real-time, extending the duration of feeding. To further analyze the mechanism of taste in regulating the feeding process, the experiment also conducted a “brief-access taste test” using the Davis Rig system to investigate the response of mice to different tastes.

2. Experimental Subjects and Samples

The experiment involved mice, recording the activity of AGRP neurons during the consumption of Ensure liquid diet and exploring the regulatory effects of sweet and fatty tastes on AGRP neurons. Furthermore, the study tested different non-nutritive substances (such as sweeteners and fat mimetic oils) to analyze whether there exists taste signal inhibition independent of nutritional status.

3. Data Analysis Methods

Experimental data were collected using various techniques, including fiber photometry for real-time recording of neuronal activity. Data analysis primarily used z-score standardization to quantify the dynamic changes in AGRP neurons under different feeding states, with a randomized experimental design to exclude interference from external factors. Through optogenetic experiments, the causal relationship between AGRP neuron activity under closed-loop control and feeding behavior was verified.

IV. Main Research Results

1. Instantaneous Inhibitory Response of AGRP Neurons to Food Taste

The experiment found that AGRP neuron activity was significantly inhibited when mice encountered food taste. Specifically, the inhibition of AGRP neurons occurred at the first instance of food licking and persisted throughout each feeding session. This inhibitory response was independent of the nutritional status of the mice and was not dependent on gastrointestinal negative feedback, but was directly triggered by taste signals. It is noteworthy that this taste-induced inhibition was particularly pronounced for high-calorie foods and the taste of sweeteners.

2. Relationship Between AGRP Neuron Inhibition and Feeding Termination

Using closed-loop optogenetic stimulation, the study further discovered that blocking the instantaneous inhibition of AGRP neurons significantly extended the feeding time of mice. This indicates that the inhibition of AGRP neurons may play a role in regulating feeding termination during feeding. This mechanism differs from previous “sustained hunger” research results because, in this study, the effect of closed-loop stimulation was instantaneous and did not produce prolonged hunger responses. This also reveals an essential distinction in the role of AGRP neurons in regulating satiety during the onset and continuation of feeding.

3. Taste Feedback Integration Function of DMH-LEPR Neurons

In further experiments, the research team recorded the activity of neurons expressing leptin receptors (LEPR neurons) located in the dorsomedial hypothalamus (DMH). The results showed that DMH-LEPR neurons exhibited significant temporal activation responses to sweet and fatty tastes, showing activity patterns opposite to AGRP neurons at each instance of food licking. The activation responses of DMH-LEPR neurons demonstrated specificity preferences for different taste cues, allowing them to regulate the negative feedback of AGRP neurons under different taste stimuli.

4. Synergistic Effect of Taste and Gastrointestinal Signals

To explore the synergistic effects of taste and gastrointestinal signals, the research team conducted gastric nutrient infusion experiments on mice. The results indicated that the presence of nutrients could amplify the activation effects of taste signals on DMH-LEPR neurons, with response strength increasing with the duration of feeding. This synergistic effect provides the neural mechanism for how taste and gastrointestinal signals co-promote satiety.

V. Research Significance and Value

1. Revealing the New Function of Taste in Negative Feedback Control of Feeding

The study discovered the negative feedback regulatory role of taste signals in the feeding process, changing the traditional perception of taste merely as a positive feedback signal. Taste signals are not only motivational for feeding but also play a key role in the termination of feeding, offering a new perspective for understanding the role of food taste in eating behavior, particularly valuable for designing taste-regulated dietary control strategies.

2. Dynamic Regulatory Mechanism of AGRP and DMH-LEPR Neurons

By exploring the interaction between AGRP neurons and DMH-LEPR neurons during the feeding process, the research revealed the synergistic role of two types of neurons in taste feedback and feeding termination. AGRP neurons are responsible for inhibiting feeding motivation, while DMH-LEPR neurons integrate taste cues, providing specific evidence for how neural circuits regulate satiety during feeding.

3. Multidimensional Neural Regulation Model of Taste Feedback

The study showed that DMH-LEPR neurons could integrate multiple taste and nutritional signals from the oral cavity and gastrointestinal tract to form comprehensive food evaluation. This regulatory mechanism offers references for understanding how animals regulate feeding behavior under multiple sensory feedbacks, with guiding significance for future studies on the neural basis of eating behavior.

VI. Research Highlights and Innovations

1. Negative Feedback Role of Taste in Feeding Termination

This study revealed the critical role of taste signals in suppressing the feeding process, breaking the traditional notion of taste as purely positive feedback, providing a new theoretical framework for understanding feeding regulation.

2. Closed-Loop Optogenetic Manipulation of AGRP Neurons

Through closed-loop optogenetic manipulation, the study verified the immediate regulatory effect of taste-dependent inhibition of AGRP neurons on feeding behavior, proving the regulatory role of taste signals in satiety during feeding.

3. Multidimensional Taste Integration by DMH-LEPR Neurons

The discovery of DMH-LEPR neurons in the study indicated that different taste signals were integrated through various neuronal subgroups, providing new research perspectives for the synergistic regulation of taste and nutritional signals.

VII. Conclusion and Outlook

The study makes important contributions to the regulation of feeding behavior by taste signals. It not only reveals the negative feedback function of taste in feeding termination but also clarifies the critical roles of AGRP neurons and DMH-LEPR neurons in the hypothalamus. This finding helps to understand the multifaceted role of food taste in satiety and feeding control. In the future, further exploration of the downstream mechanisms of these neural circuits, as well as how other sensory signals interact with taste signals to regulate feeding behavior, will provide a theoretical basis for solving problems like obesity and eating disorders.