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GDF15 Expression in Thermogenic Adipocytes Regulates Energy Homeostasis in a Sex-dependent Manner

ABSTRACT: Diet-induced obesity (DIO) induces growth differentiation factor 15 (GDF15) in various tissues, leading to increased GDF15 serum levels. The liver is the primary source of circulating GDF15 during DIO, but other tissues are also required. We investigated whether brown adipose tissue (BAT) contributes to GDF15 circulating levels and whether Gdf15 induction in BAT regulates systemic metabolism during DIO. We generated mice with selective Gdf15 deletion in thermogenic adipocytes (KO) and subjected them to 12 weeks of high-fat diet (HFD) feeding. Although in ad-libitum fed conditions GDF15 serum levels were unchanged between genotypes regardless of sex, female KO mice demonstrated reduced food intake, increased mitochondrial fatty acid oxidation in BAT, and were resistant to DIO, which was prevented by ovariectomy. Conversely, male KO mice demonstrated increased food intake, reduced mitochondrial respiratory capacity, and increased fibro-inflammation in BAT, resulting in increased body weight and fat mass accrual. Together, our data show that Gdf15 expression in BAT is required to regulate energy metabolism in mice in a sex-dependent manner.

ORGANISM(S): Mus musculus

PROVIDER: GSE296580 | GEO | 2025/12/31

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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GDF15 Expression in Thermogenic Adipocytes Regulates Energy Homeostasis in a Sex-dependent Manner

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