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Aims/hypothesisInterleukin-6 is an inflammatory cytokine with pleiotropic effects upon nutrient homeostasis. Many reports show that circulating IL6 correlates with obesity and contributes to insulin resistance; however, IL6 can promote energy expenditure that improves glucose homeostasis.MethodsWe investigated nutrient homeostasis in C57BL/6J mice with sustained circulating human IL6 (hIL6) secreted predominantly from brain and lung (hIL6tg mice).ResultsThe hIL6tg mice displayed no features of systemic inflammation and were more insulin-sensitive than wild-type mice. On a high-fat diet, hIL6tg mice were lean, had low leptin concentrations, consumed less food and expended more energy than wild-type mice. Like ob/ob mice, the ob/obIL6 mice (generated by intercrossing ob/ob and hIL6tg mice) were obese and glucose-intolerant. However, low-dose leptin injections increased physical activity and reduced both body weight and food intake in ob/obIL6 mice, but was ineffective in ob/ob mice. Leptin increased hypothalamic signal transducer and activator of transcription-3 phosphorylation in ob/obIL6 mice, whereas ob/ob mice barely responded.Conclusions/interpretationHuman IL6 enhanced central leptin action in mice, promoting nutrient homeostasis and preventing diet-induced obesity.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-009-1580-8) contains supplementary material, which is available to authorised users.

Highlights d Human b cell dysfunction induced by metabolic stress may be persistent or transient d Specific transcriptomic changes associate with durable or reversible damage d Type 2 diabetes (T2D) b cells have several functional and molecular alterations d T2D and irreversibly or temporarily impaired b cells share key transcriptome traits

The prevalence of type 2 diabetes mellitus in the Oji-Cree of northwestern Ontario is the third highest in the world. A private mutation, G319S, in HNF1A, which encodes hepatic nuclear factor-1␣ (HNF-1␣), was associated with Oji-Cree type 2 diabetes and was found in Ϸ40% of affected subjects. The G319S mutation reduced the in vitro ability of HNF-1␣ to activate transcription by Ϸ50%, with no effect on DNA binding or protein stability. There was no evidence of a dominant negative effect of the mutant protein. The impact of the G319S mutation at the population level was assessed by classifying subjects with type 2 diabetes according to HNF1A genotype and plotting the cumulative age of onset of diabetes. Disease onset was modeled satisfactorily by two-parameter sigmoidal functions for all diabetic subjects and all three HNF1A genotypes. Pairwise statistical comparisons showed significant between-genotype differences in t50 (all P < 0.00001), corresponding to the age at which half the subjects had become diabetic. Each dose of G319S accelerated median disease onset by Ϸ7 years. Thus, the transactivation-deficient HNF1A G319S mutation affects the dynamics of disease onset. The demonstration of a functional consequence for HNF1A G319S provides a mechanistic basis for its strong association with Oji-Cree type 2 diabetes and its unparalleled specificity for diabetes prediction in these people, in whom diabetes presents a significant public health dilemma. The findings also show that HNF1A mutations can be associated with typical adult-onset insulin-resistant obesity-related diabetes in addition to maturity-onset diabetes of the young.