Title
Leptin deficiency unmasks the deleterious effects of impaired peroxisome proliferator-activated receptor γ function (P465L PPARγ) in mice
Author
Gray, S.L.
Dalla Nora, E.
Grosse, J.
Manieri, M.
Stoeger, T.
Medina-Gomez, G.
Burling, K.
Wattler, S.
Russ, A.
Yeo, G.S.H.
Chatterjee, V.K.
O'Rahilly, S.
Voshol, P.J.
Cinti, S.
Vidal-Puig, A.
TNO Preventie en Gezondheid
Publication year
2006
Abstract
Peroxisome proliferator-activated receptor (PPAR)γ is a key transcription factor facilitating fat deposition in adipose tissue through its proadipogenic and lipogenic actions. Human patients with dominant-negative mutations in PPARγ display lipodystrophy and extreme insulin resistance. For this reason it was completely unexpected that mice harboring an equivalent mutation (P465L) in PPARγ developed normal amounts of adipose tissue and were insulin sensitive. This finding raised important doubts about the interspecies translatability of PPARγ-related findings, bringing into question the relevance of other PPARγ murine models. Here, we demonstrate that when expressed on a hyperphagic ob/ob background, the P465L PPARγ mutant grossly exacerbates the insulin resistance and metabolic disturbances associated with leptin deficiency, yet reduces whole-body adiposity and adipocyte size. In mouse, coexistence of the P465L PPARγ mutation and the leptin-deficient state creates a mismatch between insufficient adipose tissue expandability and excessive energy availability, unmasking the deleterious effects of PPARγ mutations on carbohydrate metabolism and replicating the characteristic clinical symptoms observed in human patients with dominant-negative PPARγ mutations. Thus, adipose tissue expandability is identified as an important factor for the development of insulin resistance in the context of positive energy balance. © 2006 by the American Diabetes Association. Chemicals / CAS: insulin, 9004-10-8; Blood Glucose; Insulin, 11061-68-0; Leptin; PPAR gamma
Subject
Biology
Peroxisome proliferator activated receptor gamma
Adipose tissue
Animal cell
Animal experiment
Animal model
Animal tissue
Carbohydrate metabolism
Controlled study
Energy balance
Female
Gene expression
gene mutation
Homozygosity
Hyperphagia
Insulin resistance
Insulin sensitivity
Lipid metabolism
Lipid storage
Lipogenesis
Male
Metabolic disorder
Nonhuman
Obesity
Point mutation
Protein deficiency
Protein function
Tissue distribution
Tissue expansion
Blood
Genetics
Glucose blood level
Homozygote
Lethal gene
Metabolism
Mouse mutant
Pathology
Physiology
Adipose Tissue
Animals
Blood Glucose
Gene Expression Profiling
Genes, Lethal
Homozygote
Insulin
Insulin Resistance
Leptin
Lipid Metabolism
Mice
Mice, Obese
PPAR gamma
To reference this document use:
http://resolver.tudelft.nl/uuid:0528733d-c242-4536-83ce-287cd10f4dd2
DOI
https://doi.org/10.2337/db06-0389
TNO identifier
239520
ISSN
0012-1797
Source
Diabetes, 55 (10), 2669-2677
Document type
article