Isoform-Specific Control of Adipose Thermogenesis by the miR-27 Family Reveals Antagonism within a Polycistronic miRNA Cluster

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Abstract MicroRNAs (miRNAs) are frequently encoded within polycistronic clusters thought to function as coherent regulatory units, yet whether individual cluster members act cooperatively or exert distinct physiological effects remains unclear. miR-27a and miR-27b are closely related miRNAs located within separate paralogous miR-23/27/24 clusters, but their in vivo relationship is unresolved. Using isoform-specific knockout models generated by precise CRISPR-based excision of individual miRNA hairpins, we defined how miR-27a and miR-27b regulate adipose thermogenesis and systemic metabolism. High-fat feeding increased miR-27a/b expression and suppressed thermogenic gene programs in subcutaneous white adipose tissue. In primary beige and brown adipocytes, loss of either isoform produced modest activation of thermogenic programs, whereas combined deletion caused additive increases in Ucp1 expression and mitochondrial DNA content. Ex vivo heat production was significantly elevated in double-knockout adipose explants relative to wild-type and single-knockout controls. In vivo , double-knockout mice exhibited increased energy expenditure and, under high-fat diet conditions, reduced adiposity with improved glucose homeostasis compared with wild-type and single-knockout mice. In contrast to metabolic dysfunction reported following whole-cluster deletion, selective miR-27 loss reveals a protective thermogenic program. These findings demonstrate that miRNA clusters need not act as coherent regulatory modules and identify miR-27a/b as a cooperative thermogenic checkpoint with therapeutic implications. Abstract Figure * CRISPR isoform-specific knockouts isolate miR-27a/b contributions to metabolism. *Dual miR-27a/b loss drives cooperative thermogenic activation. *Double knockouts enhance energy expenditure and metabolic fitness in diet-induced obesity. *miR-27a/b deletion reveals that clustered miRNAs can exert non-coherent regulatory roles.

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