Obesity genes and insulin resistance.
OBJECTIVE
The exploding prevalence of insulin resistance and Type 2 diabetes (T2D) linked to obesity has become an alarming public health concern. Worldwide, approximately 171 million people suffer from obesity-induced diabetes and public health authorities expect this situation to deteriorate rapidly. An interesting clinical population of 'metabolically healthy but obese' (MHO) cases is relatively protected from T2D and its associated cardiovascular risk. The molecular basis for this protection is not well understood but is likely to involve reduced inflammatory responses. The inflammatory cells and pathways that respond to overnutrition are the primary subject matter for this review.


RESULTS
The chance discovery of a genetic mutation in the Brd2 gene, which is located in the class II major histocompatibility complex and makes mice enormously fat but protects them from diabetes, offers revolutionary new insights into the cellular mechanisms that link obesity to insulin resistance and T2D. These Brd2-hypomorphic mice have reduced inflammation in fat that is normally associated with insulin resistance, and resemble MHO patients, suggesting novel therapeutic pathways for obese patients at risk for T2D.


CONCLUSIONS
Deeper understanding of the functional links between genes that control inflammatory responses to diet-induced obesity is crucial to the development of therapies for obese, insulin-resistant patients.
Belkina
Anna C
AC
Boston Nutrition Obesity Research Center, Cancer Research Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Denis
Gerald V
GV
D054392:Adipokines / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000209:etiology / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000453:epidemiology / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism; D014157:Transcription Factors; D000092468:Bromodomain Containing Proteins
D054392:Adipokines; D002868:Chromosomal Proteins, Non-Histone; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C490844:Brd2 protein, mouse