Non-human animal model for obesity and uses thereof
AssigneeOklahoma Medical Research Foundation
InventorsMiles B. Brennan, Ute Hochgeschwender
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Abstract
Described is a genetically modified non-human animal model for studying the peripheral and central pathways of energy homeostasis. Also disclosed are methods of identifying compounds for regulating such pathways and a Pomc mutant mouse.
Claims46
A genetically modified mouse useful for studying peripheral and central pathways of energy homeostasis, said genetically modified mouse comprising a genetic modification within two alleles of its Pomc locus, the genetic modification comprising a deletion, a substitution, or a modification of exon 3 of the Pomc locus or a deletion, a substitution, or a modification preventing or reducing expression of exon 3 of the Pomc locus, wherein said genetic modification results in an absence of proopiomelanocortin (Pomc) peptide action in said mouse and further wherein the genetic modification results in the mouse having obesity and showing a loss in body weight when treated peripherally with a stable MSH agonist.
A method for studying the molecular and biochemical events associated with obesity, comprising:
- a. harvesting cells, tissues or body fluids from a genetically modified mouse comprising a genetic modification within two alleles of its Pomc locus, the genetic modification comprising a deletion, a substitution, or a modification of exon 3 of the Pomc locus or a deletion, a substitution, or a modification of another region of the Pomc locus preventing or reducing expression of exon 3 of the Pomc locus, wherein said genetic modification results in an absence of proopiomelanocortin (Pomc) peptide action in said mouse and further wherein the genetic modification results in the mouse having obesity and showing a loss in body weight when treated peripherally with a stable MSH agonist;
- and,
- b. comparing said cells, tissues or body fluids from said genetically modified mouse to cells, tissues or body fluids from a wild-type sibling of said genetically modified mouse.
A method to identify compounds useful in regulating peripheral and central pathways of energy homeostasis, comprising:
- a. administering a compound to be evaluated to a genetically modified mouse comprising a genetic modification within two alleles of its Pomc locus, the genetic modification comprising a deletion, a substitution, or a modification of exon 3 of the Pomc locus or a deletion, a substitution, or a modification of another region of the Pomc locus preventing or reducing expression of exon 3 of the Pomc locus, wherein said genetic modification results in an absence of proopiomelanocortin (Pomc) peptide action in said mouse and further wherein the genetic modification results in the mouse having obesity and showing a loss in body weight when treated peripherally with a stable MSH agonist;
- and,
- b. evaluating physiological changes in said genetically modified mouse as compared to a mouse selected from the group consisting of (a) a second genetically modified mouse comprising a genetic modification within at least one allele of its Pomc locus, wherein said genetic modification results in a reduction in proopiomelanocortin (Pomc) peptide action in said mouse;
- and (b) a third mouse having a genome comprising a wild-type Pomc locus at two alleles.
A method of producing a genetically modified mouse useful for studying peripheral and central pathways of energy homeostasis, comprising:
- a. introducing into an embryonic stem cell of a mouse a targeting vector comprising a Pomc locus containing a modification of a nucleic acid sequence sufficient to result in a reduction in proopiomelanocortin (Pomc) peptide action in said mouse, the modification comprising a deletion, a substitution, or a modification of exon 3 of the Pomc locus or a deletion, a substitution, or a modification preventing or reducing expression of exon 3 of the Pomc locus;
- and,
- b. obtaining progeny having two alleles containing said modification stably incorporated into their genome, wherein said modification of said nucleic acid sequence results in an absence of expression of proopiomelanocortin (Pomc) peptides by said mouse and further wherein the genetic modification results in the mouse having obesity and showing a loss in body weight when treated peripherally with a stable MSH agonist.
A genetically modified mouse useful for studying peripheral and central pathways of energy homeostasis, wherein said genetically modified mouse is produced by a method comprising the steps of:
- a. isolating from a source of murine genomic DNA a nucleic acid molecule comprising SEQ ID NO:7;
- b. deleting a nucleic acid sequence comprising SEQ ID NO:7 from said nucleic acid molecule to form a genetically modified nucleic acid molecule;
- c. inserting a selectable marker into said genetically modified nucleic acid molecule to create a targeting vector,
- d. transfecting said targeting vector into embryonic stem cells;
- e. selecting embryonic stem cells from step (d) which have incorporated said targeting vector at a target locus comprising SEQ ID NO:7 by homologous recombination;
- f. inserting said embryonic stem cells selected in step (e) into non-human animal blastocysts;
- g. impregnating a female surrogate with said non-human animal blastocysts to produce said genetically modified mouse,
- wherein the genetic modification results in the mouse having obesity and showing a loss in body weight when treated peripherally with a stable MSH agonist.
Dependencies are inferred from the claim text.