Adiponectin or adipocyte complement-related protein of 30 kDa (Acrp30) is a circulating protein produced exclusively in adipocytes. Circulating Acrp30 levels have been associated with insulin sensitivity in adult mice and humans, yet the Acrp30 profile over the lifespan and its hormonal regulation in vivo have not been previously described. Hence, we set forth to determine whether hormonal and metabolic changes associated with sexual maturation, reproduction, aging, and calorie restriction affect Acrp30. In mice, Acrp30 levels increase during sexual maturation by 4-fold in males and 10-fold in females. Neonatal castration (CX) allows Acrp30 of adults to reach female levels. CX in adults does not lead to female Acrp30 levels unless glucocorticoid exposure is elevated simultaneously by implant. Ovariectomy of infant mice does not interfere with the pubertal rise of Acrp30. However, ovariectomy in adults increases Acrp30. Estrogen suppressed Acrp30 in mice and 3T3-L1 adipocytes. In parallel to changes in estrogen action, Acrp30 decreased in late gestation but increased in both calorie-restricted and old (anovulatory) mice. The reduction of Acrp30 in lactating dams is consistent with a suppressive effect of prolactin and a stimulating effect of bromocriptine. In summary, Acrp30 levels in serum are under complex hormonal control and may play a key role in determining systemic insulin sensitivity under the respective conditions. Diabetes 52:268 -276, 2003

During the second part of the 20th century, Belyaev selected tame and aggressive foxes (Vulpes vulpes), in an effort known as the “farm-fox experiment”, to recapitulate the process of animal domestication. Using these tame and aggressive foxes as founders of segregant backcross and intercross populations we have employed interval mapping to identify a locus for tame behavior on fox chromosome VVU12. This locus is orthologous to, and therefore validates, a genomic region recently implicated in canine domestication. The tame versus aggressive behavioral phenotype was characterized as the first principal component (PC) of a PC matrix made up of many distinct behavioral traits (e.g. wags tail; comes to the front of the cage; allows head to be touched; holds observer’s hand with its mouth; etc.). Mean values of this PC for F1, backcross and intercross populations defined a linear gradient of heritable behavior ranging from tame to aggressive. The second PC did not follow such a gradient, but also mapped to VVU12, and distinguished between active and passive behaviors. These data suggest that 1) there are at least two VVU12 loci associated with behavior; 2) expression of these loci is dependent on interactions with other parts of the genome (the genome context) and therefore varies from one crossbred population to another depending on the individual parents that participated in the cross.

Strains of silver foxes, selectively bred at the Institute of Cytology and Genetics of the Russian Academy of Sciences, are a well established, novel model for studying the genetic basis of behavior, and the processes involved in canine domestication. Here we describe a method to measure fox behavior as quantitative phenotypes which distinguish populations and resegregate in experimental pedigrees. We defined 50 binary observations that nonredundantly and accurately distinguished behaviors in reference populations and cross-bred pedigrees. Principal-component analysis dissected out the independent elements underlying these behaviors. PC1 accounted for >44% of the total variance in measured traits. This system clearly distinguished tame foxes from aggressive and wildtype foxes. F1 foxes yield intermediate values that extend into the ranges of both the tame and aggressive foxes, while the scores of the backcross generation resegregate. These measures can thus be used for QTL mapping to explore the genetic basis of tame and aggressive behavior in foxes, which should provide new insights into the mechanisms of mammalian behavior and canine domestication.

Acute exposure to lipopolysaccharide (LPS) can cause hypoglycemia and insulin resistance; the underlying mechanisms, however, are unclear. We set out to determine whether insulin resistance is linked to hypoglycemia through Toll-like receptor-4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor B (NF B), a cell signaling pathway that mediates LPS induction of the proinflammatory cytokine tumor necrosis factor alpha (TNF␣). LPS induction of hypoglycemia was blocked in TLR4 ؊/؊ and MyD88 ؊/؊ mice but not in TNF␣ ؊/؊ mice. Both glucose production and glucose utilization were decreased during hypoglycemia. Hypoglycemia was associated with the activation of NF B in the liver. LPS inhibition of glucose production was blocked in hepatocytes isolated from TLR4 ؊/؊ and MyD88 ؊/؊ mice and hepatoma cells expressing an inhibitor of NF B (I B) mutant that interferes with NF B activation. Thus, LPS-induced hypoglycemia was mediated by the inhibition of glucose production from the liver through the TLR4, MyD88, and NF B pathway, independent of LPS-induced TNF␣. LPS suppression of glucose production was not blocked by pharmacologic inhibition of the insulin signaling intermediate phosphatidylinositol 3-kinase in hepatoma cells. Insulin injection caused a similar reduction of circulating glucose in TLR4 ؊/؊ and TLR4 ؉/؉ mice. These two results suggest that LPS and insulin inhibit glucose production by separate pathways. Recovery from LPS-induced hypoglycemia was linked to glucose intolerance and hyperinsulinemia in TLR4 ؉/؉ mice, but not in TLR4 ؊/؊ mice. Conclusion: Insulin resistance is linked to the inhibition of glucose production by the TLR4, MyD88, and NF B pathway. (HEPATOLOGY 2009;50:592-600.) L ipopolysaccharide (LPS) from Gram-negative bacterial infection can cause hypoglycemia and insulin resistance in both humans and mice; however, the underlying mechanisms are unclear. 1-5 Low levels of LPS exposure through gastrointestinal tract and airborne particles can also lead to insulin resistance. 6-8 Thus, insulin resistance is decreased in mice by antibiotic treatment or housing in germ-free facilities. 9,10 Insulin resistance is also decreased by gene deletion of Toll-like receptor-4 (TLR4) or cluster of differentiation 14 (CD14), a glycoprotein that binds to the extracellular portion of TLR4. [11][12][13] TLR4 is a plasma membrane protein that mediates LPS induction of inflammatory cytokines such as tumor necrosis factor alpha (TNF␣) and interleukin-1 beta (IL-1␤). 14 The main goals of this study were to (1) determine whether TLR4 and its downstream signaling targets mediate the induction of hypoglycemia by LPS and, if so, (2) determine whether the induction of hypoglycemia by TLR4 is linked to the development of insulin resistance.LPS was postulated to cause hypoglycemia through the induction of the cytokines TNF␣ and IL-1␤. 15 Given that LPS does not induce hypoglycemia in IL-1␣ Ϫ/Ϫ and IL-1␤ Ϫ/Ϫ "double-knockout" mice, LPS induction of IL-1␤ is essential. 16 Whether LPS induction of TNF␣