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Hypothalamic rat peptide gene-associated proteins (AgRP) and promelanin (POMC) have long been considered primary neuronsthat integrate hormonal and nutrient signals to maintain energy balance.
The activation of AgRP neurons promotes obesity by stimulating appetite and inhibiting energy expenditure, and inhibiting the activity of AgRP neurons causes anorexia and weight loss
.
In contrast, chronic activation of POMC neurons inhibits food intake and increases metabolic rate, preventing obesity
.
In addition, deletion of functional mutations in POMC genes can lead to overfeeding and obesity
in rodents and humans.
Leptin is a hormone secreted by white fat cells that transmits metabolic messages to the central nervous system and controls the stability
of energy and glucose.
Disruption of the function of leptin or leptin receptors (LepR) causes obesity and diabetes
.
LepR is expressed in both AgRP and POMC neurons, and leptin administration inhibits AgRP neurons while activating POMC neurons
.
Growth factor receptor-binding protein 10 (Grb10) binds to insulin receptors and insulin-like growth factor receptor 1 to regulate energy metabolism
.
Liver-specific knockout Grb10 is involved in acute endoplasmic reticulum stress-induced hepatic steatosis in mice
.
On January 3, 2023, Professor Yong Xu of Baylor College of Medicine and Professor Liu Feng of the Metabolic Syndrome Research Center of the Second Xiangya Hospital of Central South University published an article in the journal Nature Metabolism that hypothalamic Grb10 can enhance leptin signaling and promote its weight reduction effect
.
1
Lowering Grb10 in AgRP neurons enhances leptin sensitivity
Through co-immunoprecipitation experiments, the researchers found that Grb10 and LepR were bound, and the reduction of Grb10 expression by virus could inhibit leptin activation of downstream JAK2 and JAK3 signals, while overexpression of Grb10 could promote leptin activation of downstream signals, which indicated that Grb10 could enhance the leptin signaling pathwaythrough LepR.
Immunofluorescence experiments showed that the vast majority (87%) of AgRP neurons expressed Grb10, and after specifically reducing Grb10 on AgRP neurons in the arcuate nucleus of the hypothalamus through genetic tools, it could cause weight gain, reduced energy expenditure, and increased
serum leptin levels under ordinary diet.
Although not causing changes in insulin levels, glucose tolerance disorders
remain.
After specifically overexpressing Grb10 on AgRP neurons, mice lose weight, increase energy expenditure, and decrease
serum leptin levels.
Further experiments found that after 3 consecutive days of intraperitoneal injection of leptin, it could significantly inhibit feeding behavior, causing weight loss in mice, and specific overexpression of Grb10 on AgRP neurons could further aggravate the energy metabolism disorders caused by leptin, while reducing Grb10 expression could significantly alleviate leptin-induced weight loss, and these results showed that Grb10 on AgRP neurons could enhance leptin sensitivity
.
Figure 1: Knocking out Grb10 on AgRP neurons promotes obesity
2
Increasing Grb10 in POMC neurons enhances leptin sensitivity
Immunofluorescence experiments showed that almost all (95%) POMC neurons expressed Grb10, and after specifically reducing Grb10 on arcuate POMC neurons through genetic tools, it did not cause changes in energy metabolism in ordinary diet, but after high-fat diet, it could significantly accelerate weight gain, fat gain, increased serum leptin and insulin levels, and reducedenergy expenditure in mice.
After overexpressing Grb10 on POMC neurons, it can significantly alleviate the energy metabolism disorders caused by high-fat diet, reduce body weight and increase energy expenditure
.
After 2 weeks of high-fat diet, the mice were able to significantly inhibit feeding behavior after 3 consecutive days of intraperitoneal injection of leptin, causing weight loss in mice, but this effect
of leptin could be significantly blocked after knocking out Grb10 on POMC neurons.
In contrast, overexpression of Grb10 on POMC neurons further enhances the action of
leptin.
Figure 2: Knocking out Grb10 on POMC neurons promotes obesity
3
Grb10 acts on AgRP and POMC neurons through different ion channels
It has been shown that leptin can inhibit the excitability of AgRP neurons by inducing ATP-sensitive potassium ion channel current, and can regulate energy homeostasisby activating POMC neurons through transient receptor potential channels (TrpC).
Through electrophysiological experiments, the researchers found that overexpression of Grb10 on AgRP neurons can significantly enhance leptin-activated ATP-sensitive potassium channels, and ATP-sensitive potassium channel inhibitors can block the above enhancement
.
Leptin-induced TrpC channel current weakens after knocking out Grb10 on POMC neurons, while TrpC channel current is enhanced after overexpressing Grb10 on POMC neurons
.
This suggests that Grb10 can enhance the inhibitory effect of leptin on AgRP neurons through ATP-sensitive potassium channels, and the excitatory effect
of leptin on POMC neurons through TrpC channels.
summary
Leptin is considered a potential weight loss drug, but it is not widely used
due to its leptin-resistant effects.
In this review, it was found that growth factor receptor-binding protein 10 is a powerful forward regulator of leptin signaling, which can regulate the neuronal
regulation of leptin on the hypothalamus to suppress appetite and promote appetite through different ion channels.
【References】
https://doi.
org/10.
1038/s42255-022-00701-x
The images in the article are from references
