Brown adipocyte progenitors in human skeletal muscle and methods for identifying differentiation agents therefor
Inventors
Boss, Olivier D. • Giacobino, Jean-Paul
Assignees
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Publication Number
US-8455204-B2
Publication Date
2013-06-04
Expiration Date
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 invention relates to identifying an agent that induces differentiation of a brown adipocyte progenitor cell into a brown adipocyte. The method provides a brown adipocyte progenitor cell derived from skeletal muscle and characterizes the progenitor cell as positive for CD34 marker and negative for CD146 marker. The method contacts the progenitor cell with an agent and determines the presence of an indicator of differentiation into a brown adipocyte induced by the agent.
The differentiation indicator is determined in the brown adipocyte progenitor cell, including an increase in brown-adipocyte-associated markers and/or functional measures. The indicator can include expression of uncoupling protein-1 (UCP1) protein and/or UCP1 mRNA, and may include additional markers and mitochondrial-related factors such as mitochondrial transcription factor A (mtTFA) and PGC-1α (PPARγ coactivator-1α). In addition, differentiation can be indicated by uncoupled respiration, glucose utilization rate, and fatty acid oxidation rate.
The invention also supports refining the brown adipocyte progenitor cell population and narrowing the agent selection. Additional characterization can specify progenitor cells that are negative for CD45 marker and/or CD56 marker, and agent selection can be restricted to enumerated signaling/molecular target classes, including PPAR-related modulators and inhibitors, as well as other pathway-targeted factors. In at least one example, rosiglitazone is used as the agent, and differentiation is assessed using the differentiation indicator(s) described above.
Claims Coverage
Two independent claims are directed to methods for identifying agents that induce differentiation of CD34+ / CD146− brown adipocyte progenitor cells derived from skeletal muscle into brown adipocytes. The independent claims share a common structure with three inventive components: progenitor cell definition, agent contacting, and determining a differentiation indicator; dependent claims further specify marker constraints and differentiation readouts.
Differentiation-agent identification using CD34+/CD146− skeletal muscle progenitors
A method for identifying an agent that induces differentiation of a brown adipocyte progenitor cell into a brown adipocyte, comprising providing a brown adipocyte progenitor cell derived from skeletal muscle, wherein the brown adipocyte progenitor cell is positive for CD34 marker and negative for CD146 marker; contacting the brown adipocyte progenitor cell with an agent; and determining in the brown adipocyte progenitor cell the presence of an indicator of differentiation into a brown adipocyte induced by said agent.
Differentiation-agent identification using a plurality of CD34+/CD146− skeletal muscle progenitors
A method for identifying an agent that induces differentiation of a brown adipocyte progenitor cell into a brown adipocyte, comprising providing a plurality of brown adipocyte progenitor cells derived from skeletal muscle, wherein the plurality of brown adipocyte progenitor cells are positive for CD34 marker and negative for CD146 marker; contacting the plurality of brown adipocyte progenitor cells with an agent; and determining in the plurality of brown adipocyte progenitor cells the presence of an indicator of differentiation into a brown adipocyte induced by said agent.
Across the independent claims, the core inventive coverage is the identification of differentiation-inducing agents by using brown adipocyte progenitor cells derived from skeletal muscle that are characterized as CD34+ and CD146−, contacting the cells with an agent, and determining an indicator of differentiation into a brown adipocyte. Dependent claims narrow progenitor definition with additional negative markers (CD45− and/or CD56−) and specify differentiation indicators and agent classes, including rosiglitazone.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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