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Development of an advanced multiomics strategy for 2 identifying and assessing antiobesity effects of probiotics

ABSTRACT: Probiotics have shown promise in positively altering gut microbiota and can potentially improve the gut flora of individuals with obesity. Recently, the development of probiotics with “Pharmabiotic” properties, which can reduce body fat and inhibit lipid accumulation, has emerged as a notable approach for effectively combating obesity. Nevertheless, owing to the lack of a universal methodology for elucidating the molecular mechanisms of probiotics, their antiobesity effects remain largely unknown. Herein, we developed an advanced multiomics-based strategy to decipher the mechanisms by which probiotics and their derivatives curtail adipocyte lipid production to affirm their antiobesity potential. Our initial investigation assessed the impact of probiotics and their derivatives on adipocyte differentiation and lipid generation at defined differentiation stages. Leveraging these insights, we performed comprehensive multiomics analyses at selected intervals to deepen our understanding regarding the suppression mechanisms of lipid formation. This framework confirmed the antiobesity efficacy of Lactobacillus reuteri lysate, targeting early differentiation to impede branched-chain amino acid (BCAA) catabolism and reduce adipocyte lipid accumulation. Specifically, L. reuteri lysate suppressed Krüppel-like factor 5 expression in early adipocyte differentiation phases, downregulating peroxisome proliferator–activated receptor gamma expression and reducing BCAA catabolism. Concurrently, L. reuteri lysate enhanced hypoxia-inducible factor 1 alpha expression, consequently downregulating lipin-1 expression in initial adipocyte differentiation stages, thus inhibiting adipogenesis. This study underscores the efficacy of our strategy in elucidating the intricate causal dynamics between host and microbiome, advancing therapeutic development and target exploration of probiotics.

INSTRUMENT(S): Orbitrap Exploris 240, Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Sung-Hyun Jo

LAB HEAD: Yon-Gon Kim

PROVIDER: PXD050884 | Pride | 2025-02-05

REPOSITORIES: pride

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Project description:Objective: The metalloprotease ADAM17 (also called TACE) plays fundamental roles in homeostasis by shedding key signaling molecules from the cell surface. Although its importance for the immune system and epithelial tissues is well-documented, little is known about the role of ADAM17 in metabolic homeostasis. The purpose of this study was to determine the impact of ADAM17 expression, specifically in adipose tissues, on metabolic homeostasis. Methods: We used histopathology, molecular, proteomic, transcriptomic, in vivo integrative physiological and ex vivo biochemical approaches to determine the impact of adipose tissue-specific deletion of ADAM17 upon adipocyte and whole organism metabolic physiology. Results: ADAM17adipoq-cre mice exhibited a hypermetabolic phenotype characterized by elevated energy consumption and increased levels of adipocyte thermogenic gene expression. On a high fat diet, these mice were more thermogenic, while exhibiting elevated expression levels of genes associated with lipid oxidation and lipolysis. This hypermetabolic phenotype protected mutant mice from obesogenic challenge, limiting weight gain, hepatosteatosis and insulin resistance. Activation of beta-adrenoceptors by the neurotransmitter norepinephrine, a key regulator of adipocyte physiology, triggered the shedding of ADAM17 substrates, and regulated ADAM17 expression at the mRNA and protein levels, hence identifying a functional connection between thermogenic licensing and the regulation of ADAM17. Proteomic studies identified Semaphorin 4B (SEMA4B), as a novel ADAM17-shed adipokine, whose expression is regulated by physiological thermogenic cues, that acts to inhibit adipocyte differentiation and dampen thermogenic responses in adipocytes. Transcriptomic data showed that cleaved SEMA4B acts in an autocrine manner in brown adipocytes to dampen the expression of genes involved in thermogenesis, adipogenesis, and lipid uptake, storage and catabolism. Conclusion: Our findings identify a novel ADAM17-dependent axis, regulated by beta-adrenoceptors and mediated by the ADAM17-cleaved form of SEMA4B, that modulates energy balance in adipocytes by inhibiting adipocyte differentiation, thermogenesis and lipid catabolism.

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	Day2_Control_4.raw	Raw
	Day2_reuteri_1.raw	Raw

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Development of an advanced multiomics strategy for 2 identifying and assessing antiobesity effects of probiotics

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