Hypothalamic RIIβ protein kinase A is involved in the new mechanism of brown regulation of adipose tissue

On December 18, 2022, the team of researchers Zheng Ruimao of Peking University School of Basic Medicine published an online report entitled RII in the journal Advanced Science Research paper by β-PKA in GABAergic Neurons of Dorsal Median Hypothalamus Governs White Adipose
Browning.
The study reported that the dorsal-medial nucleus of the hypothalamus γ-aminobutyric acid (GABA) neuronal RII The regulation and control mechanism of β-PKA signaling on adipose tissue browning revealed the specific brain neural structure and role of PKA in the regulation of lipid metabolism homeostasis Relevant molecular omics mechanisms (see figure below).

Browning of white adipose tissue plays an important role
in optimizing lipid metabolism homeostasis.
This phenomenon refers to: the presence of a "beige adipose precursor cell" in the white adipose tissue; Factors such as cold can activate these cells, resulting in increased mitochondria in these cells.
" elevated uncoupling protein 1" (UCP1) content; In this process, the color of white adipose tissue changes from white to beige or hazel, which is called "white adipose tissue beige" or " white adipose tissue browning"
.
This process can accelerate fat catabolism, enhance the body's calorie production and energy expenditure, reduce body fat accumulation, and thus play a role
in fighting obesity.
Neurological factors are closely involved in regulating this process, but the mechanism is not clear
.
Therefore, exploring the key neural structures that regulate adipose tissue browning and analyzing its intrinsic mechanism has important theoretical significance and clinical application value
for the prevention and treatment of obesity and its complications.

Protein kinase A (PKA) is also known as cAMP-dependent protein kinase A cyclic-AMP dependent protein kinase A), which is involved in the central regulation
of lipid metabolism homeostasis in the hypothalamus.
The team's previous research found that knocking out the RII β subunit gene (RIIβKO of PKA ) will make mice have outstanding excellent metabolic phenotypes: although their feeding remains normal, the body fat content is significantly reduced, showing a low-fat state of emaciation (leanness), and can resist high-fat food-induced obesity; However, the neural and molecular mechanisms that trigger these metabolic phenotypes in RII β KO mice are unclear
.

Mechanism diagram: Hypothalamic dorsal-medial nuclear GABAergic neurons RII β-PKA signaling involved in the regulation mechanism of fat beige Image Citation: Wang ,B.
,Zhao,M.
, et al.
Advanced Science(2022)

The research team found that RII β KO mice had a significant brown phenotype of white adipose tissue, which reproduced the RIIβ gene Expressed in the dorsovenous nucleus GABAergic neurons of the hypothalamus, the browning phenotype of RI I β KO mice disappeared, which was confirmed GABAERGIC neurons in the dorsomedial nucleus of the hypothalamus are key neurons
in PKA for regulating fat browning.
Single-cell sequencing revealed that the increased activity of GABAergic neurons in the dorsomedial nucleus of the hypothalamus is one of the important central nervous mechanisms for fat browning enhancement
。 The activation of GABAergic neurons in the dorsomedial nucleus of the hypothalamus by chemogenetics and optogenetic methods can induce browning of white adipose tissue and resist obesity; Not only that, bioinformatics analysis further revealed that the PKA activity of GABAERGIC neurons in the dorsal-medial nucleus of the hypothalamus is reduced, which is triggered Molecular mechanisms
of fat browning.
The use of gene point mutation and neuropharmacological methods to inhibit the activity of GABA-epidoractysic PKA in the dorsal-medial nucleus of the hypothalamus can also induce browning of white adipose tissue and resist obesity
.

In summary, the study suggests that the PKA activity of GABAergic neurons in the dorsal-medial nucleus of the hypothalamus is reduced and the GABAergic caused by it Enhanced neuronal activity is an important driver of browning of white adipose tissue
.
This study enriches the central nervous system mechanism of PKA in regulating lipid metabolism homeostasis, and provides a new reference
for the prevention and treatment of obesity.

Dr.
Wang Bingwei, School of Basic Medical Sciences, Peking University, is the first author of the paper, and researcher Zheng Ruimao is the corresponding author
.
The research was completed on the platform of the Department of Human Anatomy and Histology and Embryology, the Institute of Neuroscience of Peking University, the Key Laboratory of Neuroscience of the Ministry of Education, and the Key Laboratory of Neuroscience of the National Health Commission, and was also supported by the National Natural Science Foundation of China, the Beijing Municipal Natural Science Foundation, and the Peking University Research Start-up Fund
。

Original link: https://doi.
org/10.
1002/advs.
202205173 (School of Basic Medical Sciences, Peking University).