Cell Journal: The brain balances how much to eat and precisely regulates blood sugar levels through these two neurons in the intestine

Written | Edited by xiao xia | Typeset by Wang Cong | Shui Chengwen As we all know, sensory neurons in the intestine control human food intake and blood sugar levels.
In obesity, intestinal-brain communication is impaired
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Although the importance of sensory neurons in gut-brain communication has been established, it is still unclear which of these cells are actually involved in the regulation of food intake and blood sugar levels
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Different sensory neurons innervating different organs/tissues of the gastrointestinal tract respond to different gut-derived signals, and neuronal activation helps to regulate food intake and glucose metabolism
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However, the identity of intestinal sensory neurons involved in the acute regulation of glucose metabolism remains unclear
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In addition, although gut-derived stimuli have been shown to activate different sensory neurons, their effects on the response to feeding and blood sugar regulation and the role of related downstream circuits in the brain remain unclear
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Recently, the research team of the Max Planck Institute in Germany published a research paper titled: Gut-brain communication by distinct sensory neurons differently controls feeding and glucose metabolism in the journal Cell Metabolism
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The research team used cross-gene targeting technology to explore the feeding and blood sugar regulation functions of different sensory neurons, and confirmed that sensory neurons innervated by different intestinal nerves control the feeding and blood sugar regulating neural circuits.
Our brains are very sensitive to the food we eat.
The response may be mediated by the interaction of neurons expressing GLP1R and GPR65
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This also provides precise targets for the treatment of metabolic diseases
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First, the research team developed a cross-gene targeting technology to study the functional neural circuits of sensory neurons that innervate the intestine
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This technology generates triple transgenic mice that express tdTomato (a red fluorescent protein) only in different sensory neurons, that is, express Dre recombinase at the same time (Nav1.
8 positive, Nav1.
8 is a kind of only in sensory neurons Expressing sodium channels) and Cre recombinase in mice
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Fluorescence in situ hybridization experiments confirmed that the technology can accurately and reproducibly cross-target the vagus nerve and spinal afferent nerve, and determine their different central projections
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In order to determine the contribution of discrete sensory neurons to intestinal-brain communication, the research team next reconstructed the peripheral innervation of the gastrointestinal organs of the triple transgenic mice
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In mice derived from the Phox2b-Cre line, they observed that PHOX2B vagal afferent nerves are concentrated in the small intestinal mucosa and muscles, supporting their key role in signal transmission from the upper digestive tract organs
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In mice derived from the Glp1r-ires-Cre and Gpr65-ires-Cre strains, the research team observed that the GLP1R and GPR65 vagal afferents showed different gastric and small intestinal innervation patterns
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In mice derived from the Wnt1-Cre line, tdTomato is distributed throughout the intestine, especially in the ileum and colon, where dense nerves innervate the muscle layer
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Compared with the PHOX2B vagus afferent nerve, the dense innervation of the ileum and colon defines the characteristics of spinal afferents
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After establishing selective intestinal innervation through GLP1R and GPR65 vagus nerve afferents, the research team learned about their feeding and glucose regulation functions
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They found that in the case of calorie deprivation, the acute activation of vagus nerve afferents by GLP1R instead of GPR65 was sufficient to reduce eating in mice.
This reduction in eating behavior is controlled by the nucleus tractus solitarius (NTS) and projected to the outside of the control eating behavior.
Neurons in the parabrachial nucleus (PB)
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In addition to eating, sensory neurons that innervate the intestine are also involved in the regulation of glucose homeostasis
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In view of this, the research team tested the acute glucose regulation function of GLP1R and GPR65 vagus nerve afferents, and found that stimulating GLP1R vagus nerve afferents reduced the blood sugar level of the fed animals
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However, after stimulating the GPR65 vagus nerve afferent, blood sugar levels increased
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The normoglycemic-hyperinsulinemic clamp experiment proved that acute activation of GLP1R vagus nerve afferent improves glucose tolerance by increasing glucose uptake in skeletal muscle
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In contrast, activation of GPR65 vagus nerve afferents increases blood sugar by increasing Pck1
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Further studies have found that the selective inactivation of GLP1R vagus nerve afferents disrupts blood glucose control during eating, which proves that GLP1R vagus nerve afferents participate in the glucose regulation of enteroendocrine hormones and are particularly important for blood glucose control during feeding
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All in all, the research has developed a Cre/Dre-based cross-targeting technology, which is widely applicable to locating and manipulating sensory neurons, helping to discover the afferent populations of vagus nerve innervated by the intestinal nerves, which control blood sugar in different ways
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GLP1R+vagus nerve transmits anorexia signals to brainstem neurons, GPR65+vagus nerve increases liver glucose production, and GLP1R+vagus nerve afferent activity is needed to control blood sugar during eating
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This technology, together with the genetically modified mouse system, can provide an advanced technology platform for the future functional research of neurons in the intestinal-brain communication under normal and disease states.

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Link to the paper: https://doi.
org/10.
1016/j.
cmet.
2021.
05.
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