Brown adipocyte progenitors in human skeletal muscle

Inventors

Boss, Olivier D. • Giacobino, Jean-Paul

Assignees

Energesis Pharmaceuticals Inc

Abstract

Brown adipose tissue (“BAT”) progenitor cells and methods for identifying BAT progenitor cells in a population of cells are provided. Methods are also provided for inducing differentiation of BAT progenitor cells into differentiated brown adipocytes, inducing expression or increased activity levels of BAT uncoupling protein-1 (“UCP1”), and for identifying agents capable of inducing differentiation of BAT progenitor cells into brown adipocytes and/or inducing expression or increased activity levels of UCP1. Differentiated brown adipocytes and agents and methods for inducing differentiation of BAT progenitor cells can be used for treatment of or the making of medicaments for the treatment of metabolic diseases or conditions in a patient such as obesity, overweight, impaired glucose tolerance, insulin-resistance, type 2 diabetes, dyslipidemia, hypertension, cardiovascular diseases, metabolic syndrome, and the like. Differentiated brown adipocytes and agents and methods for inducing differentiation of BAT progenitor cells can be used for prevention of hypothermia.

Core Innovation

The disclosed invention relates to a method for inducing differentiation of brown adipose tissue progenitor cells into brown adipocytes. The method provides a BAT progenitor cell isolated from skeletal muscle and exposes the BAT progenitor cell to a differentiation agent in vitro. The differentiation agent comprises one or more PPAR-family activators so that the agent induces the BAT progenitor cell to differentiate into a brown adipocyte.

In particular, the differentiation agent comprises a PPARγ activator, a PPARα activator, a PPARδ activator, a dual PPARα and PPARδ activator, or a pan-PPAR (α, δ, γ) activator. The disclosure also includes embodiments in which the differentiation agent is rosiglitazone. Differentiation outcomes are directed toward induction of brown adipocyte identity in vitro.

The document further characterizes BAT progenitor cells and resulting brown adipocytes using brown adipocyte markers and functional properties. UCP1-related markers and related mitochondrial and transcriptional markers are described in connection with differentiated brown adipocytes, including increased UCP1 and associated mitochondrial and metabolic readouts. The disclosure also includes assays and screening concepts for agents that induce UCP1 expression and differentiation, including a UCP1 promoter/enhancer reporter system.

Claims Coverage

The independent claim covers inducing in vitro differentiation of skeletal muscle-derived BAT progenitor cells into brown adipocytes using a differentiation agent that comprises specific PPAR-family activators. The coverage is refined by additional claims to specify particular progenitor-cell marker phenotypes and differentiation-agent selections, including rosiglitazone, and to characterize differentiated brown adipocytes by UCP1-related expression levels relative to in vivo human skeletal muscle brown adipocytes.

Overall, the claims coverage centers on using PPAR-family activators, optionally including rosiglitazone, and optionally including dual or pan-PPAR activator selections, to induce differentiation of skeletal muscle-derived BAT progenitor cells into brown adipocytes, with further claim refinements defined by progenitor marker phenotypes and brown-adipocyte characterization using UCP1-related expression levels relative to in vivo human skeletal muscle brown adipocytes.

Stated Advantages

Documented Applications