Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation

TLDR

STAT3 is widely expressed in the CNS and has been linked to neuron/glial differentiation and leptin‑mediated energy homeostasis, yet its precise physiological role remains unclear due to the absence of a direct genetic model. The study aimed to determine STAT3’s role in the CNS by creating mice with a neural‑specific disruption of STAT3 (STAT3 N‑/‑). The authors generated STAT3 N‑/‑ mice by selectively deleting STAT3 in neural tissues. STAT3 N‑/‑ mice were born at expected Mendelian ratios but many died neonatally; survivors exhibited hyperphagia, obesity, diabetes, infertility, hyperleptinemia, reduced energy expenditure, hypothermia, and altered hypothalamic neuropeptide expression, and melanocortin‑3/4 agonist treatment normalized food intake, underscoring a critical CNS role for STAT3 in energy balance and reproduction.

Abstract

Signal transducer and activator of transcription (STAT)3 is widely expressed in the CNS during development and adulthood. STAT3 has been implicated in the control of neuron/glial differentiation and leptin-mediated energy homeostasis, but the physiological role and degree of involvement of STAT3 in these processes is not defined and controversial because of the lack of a direct genetic model. To address this, we created mice with a neural-specific disruption of STAT3 (STAT3 N-/- ). Surprisingly, homozygous mutants were born at the expected Mendelian ratio without apparent developmental abnormalities but susceptible to neonatal lethality. Mutants that survived the neonatal period were hyperphagic, obese, diabetic, and infertile. Administering a melanocortin-3/4 receptor agonist abrogated the hyperphagia and hypothalamic immunohistochemistry showed a marked reduction in proopiomelanocortin with an increase in neuropeptide Y and agouti-related protein. Mutants had reduced energy expenditure and became hypothermic after fasting or cold stress. STAT3 N-/- mice are hyperleptinemic, suggesting a leptin-resistant condition. Concomitant with neuroendocrine defects such as decreased linear growth and infertility with accompanying increased corticosterone levels, this CNS knockout recapitulates the unique phenotype of db / db and ob / ob obese models and distinguishes them from other genetic models of obesity. Thus, STAT3 in the CNS plays essential roles in the regulation of energy homeostasis and reproduction.