TonEBP/NFAT5 promotes obesity and insulin resistance by epigenetic suppression of white adipose tissue beiging

Tonicity-responsive enhancer binding protein (TonEBP or NFAT5) is a regulator of cellular adaptation to hypertonicity, macrophage activation and T-cell development. Here we report that TonEBP is an epigenetic regulator of thermogenesis and obesity. In mouse subcutaneous adipocytes, TonEBP expression increases > 50-fold in response to high-fat diet (HFD) feeding. Mice with TonEBP haplo-deficiency or adipocyte-specific TonEBP deficiency are resistant to HFD-induced obesity and metabolic defects (hyperglycemia, hyperlipidemia, and hyperinsulinemia). They also display increased oxygen consumption, resistance to hypothermia, and beiging of subcutaneous fat tissues. TonEBP suppresses the promoter of beta 3-adrenoreceptor gene, a critical regulator of lipolysis and thermogenesis, in ex vivo and cultured adipocytes. This involves recruitment of DNMT1 DNA methylase and methylation of the promoter. In human subcutaneous adipocytes TonEBP expression displays a correlation with body mass index but an inverse correlation with beta 3-adrenoreceptor expression. Thus, TonEBP is an attractive therapeutic target for obesity, insulin resistance, and hyperlipidemia

Steroid receptor expression in the fish inner ear varies with sex, social status, and reproductive state

<p>Abstract</p> <p>Background</p> <p>Gonadal and stress-related steroid hormones are known to influence auditory function across vertebrates but the cellular and molecular mechanisms responsible for steroid-mediated auditory plasticity at the level of the inner ear remain unknown. The presence of steroid receptors in the ear suggests a direct pathway for hormones to act on the peripheral auditory system, but little is known about which receptors are expressed in the ear or whether their expression levels change with internal physiological state or external social cues. We used qRT-PCR to measure mRNA expression levels of multiple steroid receptor subtypes (estrogen receptors: ERα, ERβa, ERβb; androgen receptors: ARα, ARβ; corticosteroid receptors: GR2, GR1a/b, MR) and aromatase in the main hearing organ of the inner ear (saccule) in the highly social African cichlid fish <it>Astatotilapia burtoni</it>, and tested whether these receptor levels were correlated with circulating steroid concentrations.</p> <p>Results</p> <p>We show that multiple steroid receptor subtypes are expressed within the main hearing organ of a single vertebrate species, and that expression levels differ between the sexes. We also show that steroid receptor subtype-specific changes in mRNA expression are associated with reproductive phase in females and social status in males. Sex-steroid receptor mRNA levels were negatively correlated with circulating estradiol and androgens in both males and females, suggesting possible ligand down-regulation of receptors in the inner ear. In contrast, saccular changes in corticosteroid receptor mRNA levels were not related to serum cortisol levels. Circulating steroid levels and receptor subtype mRNA levels were not as tightly correlated in males as compared to females, suggesting different regulatory mechanisms between sexes.</p> <p>Conclusions</p> <p>This is the most comprehensive study of sex-, social-, and reproductive-related steroid receptor mRNA expression in the peripheral auditory system of any single vertebrate. Our data suggest that changes in steroid receptor mRNA expression in the inner ear could be a regulatory mechanism for physiological state-dependent auditory plasticity across vertebrates.</p

The African Cichlid Fish Astatotilapia burtoni Uses Acoustic Communication for Reproduction: Sound Production, Hearing, and Behavioral Significance

Sexual reproduction in all animals depends on effective communication between signalers and receivers. Many fish species, especially the African cichlids, are well known for their bright coloration and the importance of visual signaling during courtship and mate choice, but little is known about what role acoustic communication plays during mating and how it contributes to sexual selection in this phenotypically diverse group of vertebrates. Here we examined acoustic communication during reproduction in the social cichlid fish, Astatotilapia burtoni. We characterized the sounds and associated behaviors produced by dominant males during courtship, tested for differences in hearing ability associated with female reproductive state and male social status, and then tested the hypothesis that female mate preference is influenced by male sound production. We show that dominant males produce intentional courtship sounds in close proximity to females, and that sounds are spectrally similar to their hearing abilities. Females were 2–5-fold more sensitive to low frequency sounds in the spectral range of male courtship sounds when they were sexually-receptive compared to during the mouthbrooding parental phase. Hearing thresholds were also negatively correlated with circulating sex-steroid levels in females but positively correlated in males, suggesting a potential role for steroids in reproductive-state auditory plasticity. Behavioral experiments showed that receptive females preferred to affiliate with males that were associated with playback of courtship sounds compared to noise controls, indicating that acoustic information is likely important for female mate choice. These data show for the first time in a Tanganyikan cichlid that acoustic communication is important during reproduction as part of a multimodal signaling repertoire, and that perception of auditory information changes depending on the animal's internal physiological state. Our results highlight the importance of examining non-visual sensory modalities as potential substrates for sexual selection contributing to the incredible phenotypic diversity of African cichlid fishes