Metabolic consequences of lipodystrophy in mouse models

Current Opinion in Clinical Nutrition and Metabolic Care

Volumn 9, Issue 4, 2006, Pages 436-441

  Reue, Karen ^a,b   Phan, Jack ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b VA GREATER LOS ANGELES HEALTHCARE SYSTEM   (United States)

Author keywords

Adipokine; Energy expenditure; Glucose homeostasis; Inflammatory response; Insulin resistance; Lipodystrophy; Lipotoxicity; Transgenic mice

Indexed keywords

ADIPOCYTOKINE; ADIPONECTIN; CYTOKINE; FK 506 BINDING PROTEIN; INSULIN; INTERLEUKIN 6; LEPTIN; LIPID; RESISTIN; TRANSFORMING GROWTH FACTOR BETA; TRIACYLGLYCEROL; TUMOR NECROSIS FACTOR ALPHA;

ADIPOSE TISSUE; CYTOKINE PRODUCTION; DISEASE ASSOCIATION; DRUG MECHANISM; DRUG PROTEIN BINDING; DRUG TARGETING; ENERGY EXPENDITURE; ENERGY METABOLISM; EXPERIMENTAL MODEL; EXPERIMENTAL MOUSE; FATTY LIVER; GLUCOSE HOMEOSTASIS; HUMAN; HYPERGLYCEMIA; HYPERTRIGLYCERIDEMIA; IMPAIRED GLUCOSE TOLERANCE; INSULIN BLOOD LEVEL; INSULIN RELEASE; INSULIN RESISTANCE; LIPID BLOOD LEVEL; LIPID METABOLISM; LIPID STORAGE; LIPOATROPHY; LIPODYSTROPHY; METABOLIC DISORDER; METABOLIC RATE; NONHUMAN; PANCREAS ISLET BETA CELL; PANCREAS ISLET DISEASE; PROTEIN BLOOD LEVEL; REVIEW; TRIACYLGLYCEROL BLOOD LEVEL; WILD TYPE;

ADIPOSE TISSUE; ANIMALS; DISEASE MODELS, ANIMAL; ENERGY METABOLISM; HUMANS; INSULIN RESISTANCE; LIPID METABOLISM; LIPODYSTROPHY; MICE;

EID: 33746253894     PISSN: 13631950     EISSN: 15353885     Source Type: Journal    
DOI: 10.1097/01.mco.0000232904.82038.db     Document Type: Review

References (37)

1. Garg A. Acquired and inherited lipodystrophies. N Engl J Med 2004; 350:1220-1234. An excellent review of clinical and genetic aspects of human lipodystrophies.
2. Hegele RA. Phenomics, lipodystrophy, and the metabolic syndrome. Trends Cardiovasc Med 2004; 14:133-137.
3. Rudich A, Ben-Romano R, Etzion S, Bashan N. Cellular mechanisms of insulin resistance, lipodystrophy and atherosclerosis induced by HIV protease inhibitors. Acta Physiol Scand 2005; 183:75-88.
4. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004; 89:2548-2556. A recent concise overview of endocrine functions of adipose tissue.
5. Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372:425-432.
6. Unger RH. Lipotoxic diseases. Annu Rev Med 2002; 53:319-336.
7. Moitra J, Mason MM, Olive M, et al. Life without white fat: a transgenic mouse. Genes Dev 1998; 12:3168-3181.
8. Shimomura I, Hammer RE, Richardson JA, et al. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 1998; 12:3182-3194.
9. Shimomura I, Hammer RE, Ikemoto S, et al. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999; 401:73-76.
10. Gavrilova O, Marcus-Samuels B, Graham D, et al. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest 2000; 105:271-278.
11. Gavrilova O, Marcus-Samuels B, Leon LR, et al. Leptin and diabetes in lipoatrophic mice. Nature 2000; 403:850.
12. Ebihara K, Ogawa Y, Masuzaki H, et al. Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes. Diabetes 2001; 50:1440-1448.
13. Suganami T, Mukoyama M, Mori K, et al. Prevention and reversal of renal injury by leptin in a new mouse model of diabetic nephropathy. FASEB J 2005; 19:127-129. This study reports that diabetic nephropathy occurs in a mouse model of lipodystrophy, and that it can be prevented or reversed by leptin administration. This reveals that adipokines are important in preventing renal injury in diabetes, and suggests that mouse models of lipodystrophy will be useful tools for further research in this area.
14. Reitman ML. Metabolic lessons from genetically lean mice. Annu Rev Nutr 2002; 22:459-482.
15. Bluher M. Transgenic animal models for the study of adipose tissue biology. Best Pract Res Clin Endocrinol Metab 2005; 19:605-623. This excellent review describes numerous transgenic and gene-knockout mouse models with altered adipose tissue, ranging from fat ablation to obesity.
16. Wang YX, Lee CH, Tiep S, et al. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 2003; 113:159-170.
17. Luquet S, Lopez-Soriano J, Holst D, et al. Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability. FASEB J 2003; 17:2299-2301.
18. Wang YX, Zhang CL, Yu RT, et al. Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol 2004; 2:e294.
19. Chawla A, Lee CH, Barak Y, et al. PPARdelta is a very low-density lipoprotein sensor in macrophages. Proc Natl Acad Sci USA 2003; 100:1268-1273.
20. Lee CH, Chawla A, Urbiztondo N, et al. Transcriptional repression of atherogenic inflammation: modulation by PPARdelta. Science 2003; 302:453-457.
21. Cederberg A, Gronning LM, Ahren B, et al. FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell 2001; 106:563-573.
22. Kim JK, Kim HJ, Park SY, et al. Adipocyte-specific overexpression of FOXC2 prevents diet-induced increases in intramuscular fatty acyl CoA and insulin resistance. Diabetes 2005; 54:1657-1663. This study demonstrates that protection from insulin resistance in fat-depleted FOXC2 transgenic mice is associated with reduced intramuscular fatty-acyl-CoA levels, supporting a role for fatty acid metabolite accumulation in muscle as a contributor to insulin resistance.
23. Ridderstrale M, Carlsson E, Klannemark M, et al. FOXC2 mRNA expression and a 5′ untranslated region polymorphism of the gene are associated with insulin resistance. Diabetes 2002; 51:3554-3560.
24. Yang X, Enerback S, Smith U. Reduced expression of FOXC2 and brown adipogenic genes in human subjects with insulin resistance. Obes Res 2003; 11:1182-1191.
25. Di Gregorio GB, Westergren R, Enerback S, et al. Expression of FOXC2 in adipose and muscle and its association with whole body insulin sensitivity. Am J Physiol Endocrinol Metab 2004; 287:E799-E803.
26. Ogawa Y, Masuzaki H, Hosoda K, et al. Increased glucose metabolism and insulin sensitivity in transgenic skinny mice overexpressing leptin. Diabetes 1999; 48:1822-1829.
27. Tanaka T, Hidaka S, Masuzaki H, et al. Skeletal muscle AMP-activated protein kinase phosphorylation parallels metabolic phenotype in leptin transgenic mice under dietary modification. Diabetes 2005; 54:2365-2374. This study demonstrates that transgenic leptin expression leads to increased AMP kinase activity, suggesting a potential mechanism for the observed effects of leptin in ameliorating ectopic lipid accumulation and insulin resistance.
28. Oral EA, Simha V, Ruiz E, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002; 346:570-578.
29. Pajvani UB, Trujillo ME, Combs TP, et al. Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nat Med 2005; 11:797-803. This study presents the first mouse model of inducible and reversible lipodystrophy, and describes metabolic features of acute lipodystrophy uncomplicated by chronic effects in tissues other than adipose tissue.
30. Trujillo ME, Pajvani UB, Scherer PE. Apoptosis through targeted activation of caspase 8 ("ATTAC-mice"): novel mouse models of inducible and reversible tissue ablation. Cell Cycle 2005; 4:1141-1145. This review discusses findings from the inducible lipodystrophy model and potential applications of the targeted transgenic apoptotic approach.
31. Reue K, Xu P, Wang XP, Slavin BG. Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene. J Lipid Res 2000; 41:1067-1076.
32. Peterfy M, Phan J, Xu P, Reue K. Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin. Nat Genet 2001; 27:121-124.
33. Phan J, Reue K. Lipin a lipodystrophy and obesity gene. Cell Metab 2005; 1:73-83. This study characterizes altered energy metabolism in the lipin-deficient lipodystrophic fld mouse, and demonstrates that enhanced lipin expression in either adipose tissue or muscle leads to obesity, but with opposite effects on insulin sensitivity for adipose tissue compared with muscle.
34. Phan J, Peterfy M, Reue K. Biphasic expression of lipin suggests dual roles in adipocyte development. Drug News Perspect 2005; 18:5-11.
35. Lan H, Rabaglia ME, Stoehr JP, et al. Gene expression profiles of nondiabetic and diabetic obese mice suggest a role of hepatic lipogenic capacity in diabetes susceptibility. Diabetes 2003; 52:688-700.
36. Peterfy M, Phan J, Reue K. Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis. J Biol Chem 2005; 280:32883-32889.
37. Suviolahti E, Reue K, Cantor RM, et al. Cross-species analyses implicate Lipin 1 involvement in human glucose metabolism. Hum Mol Genet 2006; 15:377-386. This study represents the first report of a relationship between lipin expression levels in human adipose tissue and insulin resistance.