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Mouse adipocytes ex vivo from lean Rbm43 knockout mice

ABSTRACT: Obesity is associated with systemic inflammation that impairs mitochondrial function. These changes curtail oxidative metabolism, limiting adipocyte lipid metabolism and thermogenesis, a metabolically beneficial program that dissipates chemical energy as heat. Here, we show that PGC1⍺, a key governor of mitochondrial biogenesis, is negatively regulated at the level of its mRNA translation by the RNA-binding protein RBM43. RBM43 is induced by inflammatory cytokines and suppresses mitochondrial biogenesis in a PGC1⍺-dependent manner. In mice, adipocyte-selective Rbm43 disruption elevates PGC1⍺ translation and oxidative metabolism. In obesity, Rbm43 loss confers body weight-independent protection from glucose intolerance, adipose inflammation, and activation of the innate immune sensor cGAS-STING. We further identify a role for PGC1⍺ in safeguarding against cytoplasmic accumulation of mitochondrial DNA, a cGAS ligand. The action of RBM43 defines a translational regulatory pathway by which inflammatory signals dictate cellular energy metabolism and contribute to metabolic disease pathogenesis.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): White Fat Cell

SUBMITTER: Phillip Dumesic

LAB HEAD: Bruce Spiegelman

PROVIDER: PXD048899 | Pride | 2025-01-10

REPOSITORIES: pride

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			Action	DRS
	JM8000_20220802104826.mzIdentML	Mzid
	JM8000_20220802104826.raw	Raw
	JM8001_20220802141039.mzIdentML	Mzid
	JM8001_20220802141039.raw	Raw
	JM8002_20220802173256.mzIdentML	Mzid

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Project description:Type 2 diabetes (T2D) is major cause of mortality and morbidity. The key manifestations of this disease are insulin resistance (IR), hyperglycemia and hyperinsulinemia. Secretion of insulin from the endocrine pancreas is triggered by elevated circulating glucose and acts on skeletal muscle and adipose tissues to remove excess glucose from the blood (1). This is achieved through a series of intracellular events that trigger the translocation of vesicles containing the glucose transporter 4 (GLUT4) to the surface of skeletal muscle cells and adipocytes (2,3). This process is impaired in patients with IR or T2D and insulin fails to promote GLUT4 translocation, thus resulting in inefficient glucose uptake in storage tissue and hyperglycemia (4). Chronic hyperglycemic condition increases the risk of cardiovascular disease, stroke, neuropathy, and death (5). Previously developed insulin sensitizer like thiazolidinediones (TZDs) have proven effective in improving glycemic control, however, they significantly increase the risk of cardiovascular disease due to their agonist activity at PPAR(6-8). Consequently, identifying insulin sensitizers that restore insulin-stimulated GLUT4 translocation in diabetic patients without targeting PPAR is urgently needed. The discovery of such molecules has been challenging due to the lack of a GLUT4 translocation assay amenable to high throughput screening (HTS). For this reason, we have developed a new luminescence based HTS assay that allows real time monitoring of GLUT4 translocation in mammalian cells and further adapted the assay to measure GLUT4 translocation in live mice. Using this assay, we identified a new insulin sensitizer which greatly improves insulin-dependent glucose uptake in storage tissues and glucose tolerance in insulin resistant rodents. This new insulin sensitizers acts through interaction with the Unc119 family of proteins which are known to facilitate the transport of specific cargos (9) but had not yet been implicated in insulin action or GLUT4 translocation. This study identifies new PPAR-independent insulin sensitizers with in-vivo efficacy and identify Unc119 proteins as new targets for the treatment of T2D.

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Mouse adipocytes ex vivo from lean Rbm43 knockout mice

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