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Single-nucleus RNA sequencing elucidates DHM's therapeutic mechanisms against HFD-induced BAT dysfunction

ABSTRACT: Obesity is associated with chronic diseases such as atherosclerosis and type 2 diabetes. In obesity, brown adipose tissue (BAT) activity declines, and lipid accumulation impairs its function. Dihydromyricetin (DHM) exhibits multiple biological functions, including inhibiting adipogenesis, promoting lipolysis, suppressing mitochondrial autophagy, and exerting anti-inflammatory and antioxidant effects, collectively demonstrating significant potential in obesity prevention and treatment. However, research on DHM's mechanisms in the BAT of obese mice remains limited. In this study, we performed single-nucleus RNA sequencing (snRNA-seq) to systematically characterize obesity-induced BAT dysfunction and DHM's effects at single-cell resolution in high-fat diet (HFD)-fed C57BL/6J mice. The results demonstrated that DHM ameliorated HFD-induced brown adipocyte dysfunction by modulating energy balance in Ad3 and Ad5 adipocyte subpopulations, promoting lipolysis, suppressing pro-inflammatory factor expression, inhibiting extracellular matrix remodeling, and regulating adipocyte-perivascular cell interactions. These findings provide insights into DHM's role in preventing BAT dysfunction and support its clinical application for obesity.

ORGANISM(S): Mus musculus

PROVIDER: GSE296575 | GEO | 2025/10/02

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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Single-nucleus RNA sequencing elucidates DHM's therapeutic mechanisms against HFD-induced BAT dysfunction

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