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FOXO1-KLF10 reinforcing loop promotes adipose lipolysis to facilitate exercise-induced anti-obesity effect in male mice

ABSTRACT: Exercise is recognized to be an effective way in the combat against obesity and related metabolic disorders, but the underlying mechanism is incompletely understood. Krüppel-like factor 10 (KLF10) is a transcription factor participating in diverse biological processes. KLF10 expression is abundant in adipose tissue, but its role in obesity is not well defined. Here, we show that exercise could facilitate adipocyte-derived KLF10 expression via the SIRT1/FOXO1 pathway. Adipocyte-specific knockout of KLF10 (KLF10AKO) blunts exercise-promoted white adipose browning, energy expenditure, fat loss, and glucose tolerance in diet-induced obese (DIO) mice. On the contrary, adipocyte-specific transgenic expression of KLF10 in mice (KLF10ATG) enhanced the abovementioned metabolic benefits induced by exercise. Mechanistically, KLF10 interacts with FOXO1 and facilitates the recruitment of KDM4A to form a ternary complex on the promoter regions of the Pnpla2 and Lipe genes to promote the expression of these key lipolytic genes, therefore facilitating lipolysis to defend against DIO in mice. As a newfound downstream effector responding to exercise, adipose KLF10 could act as a potential target in the fight against obesity

ORGANISM(S): Mus musculus

PROVIDER: GSE269020 | GEO | 2024/08/25

REPOSITORIES: GEO

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Project description:Activated brown adipose tissue contributes to control of energy and glucose homeostasis in rodents and humans. Defining cell-autonomous processes underlying BAT differentiation and activation may thus reveal novel therapeutic targets for obesity and type 2 diabetes mellitus intervention. Here we show that ageing- and obesity-associated demises in BAT function coincide with down-regulation of mature microRNAs in BAT in the presence of reduced expression of the critical microRNA processing enzyme Dicer1. To mimic this partial down-regulation of microRNA processing in obesity and ageing, we inactivated one allele of Dicer1 selectively in BAT of mice. BAT- restricted heterozygosity of Dicer1 caused glucose intolerance in lean mice and aggravated diet-induced-obesity (DIO)-evoked deterioration of glucose homeostasis. Using combinatorial analyses of altered microRNA-expression in BAT during in vitro preadipocyte commitment and mouse models of progeria, longevity and DIO, we identified 23 microRNAs dysregulated among these conditions. Of these, we identified miR-328 as a novel regulator of BAT differentiation. miR-328 over-expression promotes BAT-differentiation and impairs muscle progenitor commitment, while reducing miR-328 expression blocks BAT specification. We validated the ß-Secretase Bace1 as a target of miR-328, which is consequently over-expressed in BAT of obese and premature ageing mice. Reducing Bace1 expression enhances brown adipocyte, while impairing myogenic differentiation in vitro. In vivo small-molecule Bace1 inhibition in obese mice delayed DIO-induced weight gain, ameliorated obesity-associated deterioration of glucose metabolism and improved insulin sensitivity. Collectively, these experiments reveal reduced Dicer1-miR-328-Bace1 axis in presence of generalized impairment of microRNA processing in ageing and obesity as a novel determinant of ageing- and obesity-associated decline in BAT function. This may define in vivo Bace1-inhibition as an innovative therapeutic approach to not only target age-related neurodegenerative diseases but at the same time improving age-related impairment of BAT-function and metabolism. C57BL/6 mice ( 4 weeks of age) were treated with a calory-rich, high-sugar high-fat diet (HFD) for a course of 4 weeks. Then groups were stratified and one group continued to receive HFD (BAT13-15) or HFD supplemented with an experimental small-molecule Bace 1 inhibitor (BAT17, 33, 35).

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FOXO1-KLF10 reinforcing loop promotes adipose lipolysis to facilitate exercise-induced anti-obesity effect in male mice

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