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Leptin deficiency unmasks the deleterious effects of impaired peroxisome proliferator-activated receptor γ function (P465L PPARγ) in mice

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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.
Institution: TNO Preventie en Gezondheid
Source:Diabetes, 10, 55, 2669-2677
Identifier: 239520
doi: doi:10.2337/db06-0389
Keywords: 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


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