HOXA5 Participates in Brown Adipose Tissue and Epaxial Skeletal Muscle Patterning and in Brown Adipocyte Differentiation

Abstract

Brown adipose tissue (BAT) plays critical thermogenic, metabolic and endocrine roles in mammals, and aberrant BAT function is associated with metabolic disorders including obesity and diabetes. The major BAT depots are clustered at the neck and forelimb levels, and arise largely within the dermomyotome of somites, from a common progenitor with skeletal muscle. However, many aspects of BAT embryonic development are not well understood. Hoxa5 patterns other tissues at the cervical and brachial levels, including skeletal, neural and respiratory structures. Here, we show that Hoxa5 also positively regulates BAT development, while negatively regulating formation of epaxial skeletal muscle. HOXA5 protein is expressed in embryonic preadipocytes and adipocytes as early as embryonic day 12.5. Hoxa5 null mutant embryos and rare, surviving adults show subtly reduced iBAT and sBAT formation, as well as aberrant marker expression, lower adipocyte density and altered lipid droplet morphology. Conversely, the epaxial muscles that arise from a common dermomyotome progenitor are expanded in Hoxa5 mutants. Conditional deletion of Hoxa5 with Myf5/Cre can reproduce both BAT and epaxial muscle phenotypes, indicating that HOXA5 is necessary within Myf5-positive cells for proper BAT and epaxial muscle development. However, recombinase-based lineage tracing shows that Hoxa5 does not act cell-autonomously to repress skeletal muscle fate. Interestingly, Hoxa5-dependent regulation of adipose-associated transcripts is conserved in lung and diaphragm, suggesting a shared molecular role for Hoxa5 in multiple tissues. Together, these findings establish a role for Hoxa5 in embryonic BAT development.

Hoxa5 Inhibits the Proliferation and Induces Adipogenic Differentiation of Subcutaneous Preadipocytes in Goats

“…It has also been shown that Hoxa5 counteracts stem cell traits through inhibiting Wnt signaling in colorectal cancer [ 24 ]. Meanwhile, previous studies also demonstrated that Hoxa5 is required for adipose tissue development [ 25 ] and is a positive regulator of adipogenesis both in humans and mice [ 26 , 27 , 28 ]. In 3T3-L1 preadipocyte, Hoxa5 influences adipogenesis by positive transcription regulation of the fatty-acid binding protein 4 (FABP4), which is the master adipogenesis regulator [ 29 ].…”

Mevalonate biosynthesis pathway regulates the development and survival of brown adipocytes

“…Previous studies have shown that Ewing sarcoma, bone-morphogenic protein 7, and homeobox A5 are critical regulators of brown adipogenesis in cultured cells, and its loss of function reduces BAT mass in mice. 54 , 55 , 56 , 57 These previous reports clearly indicate that the regulatory mechanisms of brown adipogenesis in cultured cells are closely related to BAT development in vivo . Therefore, MVA pathway–mediated regulation of brown adipocyte differentiation is thought to be important for BAT development in vivo .…”

Characterization of a novel Hoxa5eGFP mouse line

“…In the skeletal system, Hoxa5 expression is in vertebral cartilage condensations, anterior rib condensations, and the sternal mesenchyme from E12.5 through E16.5 23,26‐29 . Hoxa5 expression has also been reported in brown adipose tissue from E14.5 to E18.5 28,30 . Within the lung, Hoxa5 is exclusively expressed in the mesenchyme, and not in the epithelium, during development 19 …”