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Editor | Enzyme Hypothalamus is considered to be the center of dietary regulation
.
Orexin neurons are mainly located in the lateral hypothalamus and play an important regulatory role in the homeostasis of energy metabolism
.
Previous studies have shown that Ox1R and Ox2R have different regulatory effects on energy metabolism
.
The concentration of Orexin in human cerebrospinal fluid is negatively correlated with the concentration of blood glucose; overexpression of Orexin in mice can increase the metabolic rate and resist overeating obesity, but the specific mechanism is still unclear
.
The 5-HT neurons located in the raphe nucleus (RN) are distributed along the midline of the brainstem, extending from the midbrain, pons to the medulla oblongata, and have extensive regulatory effects on energy metabolism, emotions, and behavior
.
5-HT neurons have obvious polymorphisms
.
The 5-HT neurons in different nuclei in the raphe nucleus group are different in morphology, electrophysiological characteristics, neural network and function
.
Recently, Nature Communications published a paper from the research group of Christine Hausen at the Max Planck Institute of Metabolism in Cologne, Germany: Orexin receptors 1 and 2 in serotonergic neurons differentially regulate peripheral glucose metabolism in obesity (first author Dr.
Xiao Xing)
.
This study found that Orexin acts on the orexin receptors Ox1R and Ox2R on central serotonin (5-HT) neurons, and regulates peripheral glucose metabolism through different mechanisms
.
The study systematically analyzed the distribution of Ox1R and Ox2R in 5-HT neurons using multi-channel fluorescence in situ hybridization, electrophysiology, calcium imaging, and single-cell sequencing
.
Ox1R is mainly expressed in the dorsal part of the dorsal raphe nucleus (DRD), while Ox2R is mainly expressed in the ventral part of the dorsal raphe nucleus (DRV)
.
The 5-HT neurons in the ventral side of the central raphe nucleus (MRV) and raphe pallidus (RPa) in the medulla oblongata express only Ox1R but not Ox2R
.
The author made Ox1R flox and Ox2R flox mice, and specifically knocked out Ox1R or Ox2R in 5-HT neurons by crossing with SERT-Cre mice to study its effect on energy metabolism in mice
.
After conditionally knocking out Ox1R or Ox2R in 5-HT neurons, mice fed a normal diet showed no significant changes in body weight, insulin tolerance and glucose tolerance
.
Obese mice on a high-fat diet have a tendency to decrease glucose tolerance when 5-HT neurons lack Ox1R, while in the absence of Ox2R in 5-HT neurons, the glucose tolerance of obese mice Receptivity increased significantly
.
Through the hyperinsulinemic-positive glucose clamp experiment, the authors further verified that conditionally knocking out Ox1R or Ox2R in 5-HT neurons reduced or enhanced insulin sensitivity in obese rats on a high-fat diet, respectively
.
In this experiment, conditionally knocking out Ox1R in 5-HT neurons did not change the production of hepatic glucose and reduced the glucose uptake of brown adipose tissue and thigh skeletal muscle; on the contrary, conditionally knocking out Ox2R in 5-HT neurons Reduce liver glucose production without significant changes in glucose uptake in peripheral tissues (brown adipose tissue, white adipose tissue and thigh skeletal muscle)
.
Gene sequencing showed that the inflammatory response in the brown adipose tissue of obese mice that conditionally knocked out Ox1R was enhanced, which may be due to the whitening of the brown adipose tissue
.
Indeed, H&E staining, electron microscopy imaging, real-time quantitative PCR, protein semi-quantification and other tests found that compared with the gene control group, the brown adipose tissue of the mice in this group increased fat, UCP-1 decreased, and mitochondrial respiration decreased.
.
Obese mice with conditionally knocked out Ox2R mainly showed a corresponding increase in liver p-AktSer473, which represents an increase in insulin sensitivity compared to the gene control group
.
Next, the author injected the adenovirus carrying hChR2-EYFP that relies on Cre recombinase into the lateral hypothalamus of orexin-cre mice, so that orexin neurons specifically express hChR2
.
Through the fluorescence tracking of EYFP, it was found that orexin neurons have a large number of nerve fiber projections in DR, MR and Rpa, and they have good co-labeling with 5-HT neurons
.
By optogenetic technology to activate orexin neurons, experiments found that the glucose tolerance of mice was weakened, and their insulin sensitivity also tended to weaken
.
Light stimulation activates orexinergic nerve fibers projected to RPa and enhances grape wine tolerance in mice
.
It is worth noting that only Ox1R is expressed in 5-HT neurons of RPa
.
Reverse fluorescence tracking showed that different groups of orexin neurons projected to DR or RPa, which further provided anatomical basis for Ox1R and Ox2R in 5-HT neurons to play different roles in peripheral glucose metabolism
.
In summary, this study found that Ox1R and Ox2R have different expressions on 5-HT neurons in different nuclei of the raphe nucleus, and they regulate glucose metabolism through different peripheral organs
.
This study provides more evidence to explain the two-way regulatory effect of orexin on peripheral glucose found in previous studies, and at the same time provides more theoretical support for obesity treatment with orexin or 5-HT system as the target
.
Original link: https:// Plate maker: Notes for reprinting on the eleventh [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is allowed, the author has all legal rights, and offenders must be investigated
.
.
Orexin neurons are mainly located in the lateral hypothalamus and play an important regulatory role in the homeostasis of energy metabolism
.
Previous studies have shown that Ox1R and Ox2R have different regulatory effects on energy metabolism
.
The concentration of Orexin in human cerebrospinal fluid is negatively correlated with the concentration of blood glucose; overexpression of Orexin in mice can increase the metabolic rate and resist overeating obesity, but the specific mechanism is still unclear
.
The 5-HT neurons located in the raphe nucleus (RN) are distributed along the midline of the brainstem, extending from the midbrain, pons to the medulla oblongata, and have extensive regulatory effects on energy metabolism, emotions, and behavior
.
5-HT neurons have obvious polymorphisms
.
The 5-HT neurons in different nuclei in the raphe nucleus group are different in morphology, electrophysiological characteristics, neural network and function
.
Recently, Nature Communications published a paper from the research group of Christine Hausen at the Max Planck Institute of Metabolism in Cologne, Germany: Orexin receptors 1 and 2 in serotonergic neurons differentially regulate peripheral glucose metabolism in obesity (first author Dr.
Xiao Xing)
.
This study found that Orexin acts on the orexin receptors Ox1R and Ox2R on central serotonin (5-HT) neurons, and regulates peripheral glucose metabolism through different mechanisms
.
The study systematically analyzed the distribution of Ox1R and Ox2R in 5-HT neurons using multi-channel fluorescence in situ hybridization, electrophysiology, calcium imaging, and single-cell sequencing
.
Ox1R is mainly expressed in the dorsal part of the dorsal raphe nucleus (DRD), while Ox2R is mainly expressed in the ventral part of the dorsal raphe nucleus (DRV)
.
The 5-HT neurons in the ventral side of the central raphe nucleus (MRV) and raphe pallidus (RPa) in the medulla oblongata express only Ox1R but not Ox2R
.
The author made Ox1R flox and Ox2R flox mice, and specifically knocked out Ox1R or Ox2R in 5-HT neurons by crossing with SERT-Cre mice to study its effect on energy metabolism in mice
.
After conditionally knocking out Ox1R or Ox2R in 5-HT neurons, mice fed a normal diet showed no significant changes in body weight, insulin tolerance and glucose tolerance
.
Obese mice on a high-fat diet have a tendency to decrease glucose tolerance when 5-HT neurons lack Ox1R, while in the absence of Ox2R in 5-HT neurons, the glucose tolerance of obese mice Receptivity increased significantly
.
Through the hyperinsulinemic-positive glucose clamp experiment, the authors further verified that conditionally knocking out Ox1R or Ox2R in 5-HT neurons reduced or enhanced insulin sensitivity in obese rats on a high-fat diet, respectively
.
In this experiment, conditionally knocking out Ox1R in 5-HT neurons did not change the production of hepatic glucose and reduced the glucose uptake of brown adipose tissue and thigh skeletal muscle; on the contrary, conditionally knocking out Ox2R in 5-HT neurons Reduce liver glucose production without significant changes in glucose uptake in peripheral tissues (brown adipose tissue, white adipose tissue and thigh skeletal muscle)
.
Gene sequencing showed that the inflammatory response in the brown adipose tissue of obese mice that conditionally knocked out Ox1R was enhanced, which may be due to the whitening of the brown adipose tissue
.
Indeed, H&E staining, electron microscopy imaging, real-time quantitative PCR, protein semi-quantification and other tests found that compared with the gene control group, the brown adipose tissue of the mice in this group increased fat, UCP-1 decreased, and mitochondrial respiration decreased.
.
Obese mice with conditionally knocked out Ox2R mainly showed a corresponding increase in liver p-AktSer473, which represents an increase in insulin sensitivity compared to the gene control group
.
Next, the author injected the adenovirus carrying hChR2-EYFP that relies on Cre recombinase into the lateral hypothalamus of orexin-cre mice, so that orexin neurons specifically express hChR2
.
Through the fluorescence tracking of EYFP, it was found that orexin neurons have a large number of nerve fiber projections in DR, MR and Rpa, and they have good co-labeling with 5-HT neurons
.
By optogenetic technology to activate orexin neurons, experiments found that the glucose tolerance of mice was weakened, and their insulin sensitivity also tended to weaken
.
Light stimulation activates orexinergic nerve fibers projected to RPa and enhances grape wine tolerance in mice
.
It is worth noting that only Ox1R is expressed in 5-HT neurons of RPa
.
Reverse fluorescence tracking showed that different groups of orexin neurons projected to DR or RPa, which further provided anatomical basis for Ox1R and Ox2R in 5-HT neurons to play different roles in peripheral glucose metabolism
.
In summary, this study found that Ox1R and Ox2R have different expressions on 5-HT neurons in different nuclei of the raphe nucleus, and they regulate glucose metabolism through different peripheral organs
.
This study provides more evidence to explain the two-way regulatory effect of orexin on peripheral glucose found in previous studies, and at the same time provides more theoretical support for obesity treatment with orexin or 5-HT system as the target
.
Original link: https:// Plate maker: Notes for reprinting on the eleventh [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is allowed, the author has all legal rights, and offenders must be investigated
.
