Hypothalamic ATF3 is involved in regulating glucose and energy metabolism in mice

Abstract

Aims/hypothesisThe pancreas and hypothalamus are critical for maintaining nutrient and energy homeostasis, and combined disorders in these organs account for the onset of the metabolic syndrome. Activating transcription factor 3 (ATF3) is an adaptive response transcription factor. The physiological role of ATF3 in the pancreas has been controversial, and its role in the hypothalamus remains unknown. To elucidate the roles of ATF3 in these organs, we generated pancreas- and hypothalamus-specific Atf3 knockout (PHT-Atf3-KO) mice in this study.MethodsWe crossed mice bearing floxed Atf3 alleles with Pdx1-cre mice, in which cre is specifically expressed in the pancreas and hypothalamus, and analysed metabolic variables, pancreatic morphology, food intake, energy expenditure and sympathetic activity in adipose tissue. We also used a hypothalamic cell line to investigate the molecular mechanism by which ATF3 regulates transcription of the gene encoding agouti-related protein (Agrp).ResultsAlthough PHT-Atf3-KO mice displayed better glucose tolerance, neither plasma glucagon nor insulin level was altered in these mice. However, these mice exhibited higher insulin sensitivity, which was accompanied by a leaner phenotype due to decreased food intake and increased energy expenditure. We also observed decreased hypothalamic Agrp expression in PHT-Atf3-KO mice. Importantly, an increase in ATF3 levels is induced by fasting or low glucose in the hypothalamus. We also showed that ATF3 interacts with forkhead box-containing protein, O subfamily 1 (FoxO1) on the Agrp promoter and activates Agrp transcription.Conclusions/interpretationOur results suggest that ATF3 plays an important role in the control of glucose and energy metabolism by regulating Agrp.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-013-2879-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

ATF3 expression is induced by low glucose in pancreatic α and β cells and regulates glucagon but not insulin gene transcription

“…3B). In contrast, as we reported previously, the staining with the H-90 antibody revealed ATF3 was expressed in both α and β cells, and was undetectable in ATF3 KO mice [10]. These results indicate that the H-90 antibody provides more reliable staining results than the C-19 antibody, and that ATF3 is actually lyzer (Fuji Film, Japan).…”

“…The membranes were probed with mouse anti-ATF3 monoclonal antibody. Mouse monoclonal antibodies against human/ mouse ATF3 were described previously [10]. To determine the relative amounts of ATF3 in each experiment, membranes were re-probed with anti-B23 (Santa Cruz, USA).…”

“…Together, these results suggest that ATF3 is a double-edged sword. We previously generated pancreas-and hypothalamus-specific ATF3 knockout mice and showed that these mice displayed better glucose tolerance and higher insulin sensitivity due to a lean phenotype; although, neither plasma insulin nor glucagon levels were changed [10].…”

“…We previously described the construction of pcDNA3.1-Flag-mATF3 and Ad-ATF3 [10]. pGL3-mGlu (wt) and pGL3-mGlu (mt) harboring a mutated CRE/ATF binding site were gifts from D.F.…”

“…The generation of pancreas-and hypothalamus-specific ATF3 KO mice was described previously [10]. Mice were housed in individual cages in a temperaturecontrolled facility with a 12-h light, 12-h dark cycle.…”