Hypothalamic APPL2 Acts as A Key Mediator in Maintaining Energy Homeostasis by Controlling Thermogenesis in Subcutaneous White Adipose Tissue

Abstract

ObjectiveTo investigate the role of hypothalamic APPL2, a close homolog of APPL1 (which has been reported to have regulatory effects on glucose metabolism), in regulation of energy metabolism.IntroductionInduction of browning in white adipose tissue (WAT), defined by transformation from white adipocytes to brown adipocytes, not only promotes adaptive thermogenesis but acts as a defensive mechanism to protect against obesity and its related metabolic disorders. Browning is tightly controlled by the cross‐talk between the energy controlling center hypothalamus and WAT, yet the underlying mechanism is unclear. In this study, we investigated whether the adaptor protein APPL2, a key player in adiponectin and insulin signaling, controls browning by mediating the cross‐talk between hypothalamus and WAT.MethodAPPL2flox/flox mice were crossed with rat insulin promoter Cre transgenic mice to generate hypothalamus and pancreatic β cell specific APPL2 knockout (RIP‐APPL2‐KO) mice, or locally injected with adenovirus‐associated virus (AAV) encoding Cre into ventromedial hypothalamus to generate APPL2 hypothalamus specific knockout mice. Basic metabolic parameters were monitored for 24 weeks. Cold challenge was employed to induce browning in the above mice.ResultsRIP‐APPL2‐KO mice displayed increased adiposity accompanied by a dramatic reduction of oxygen consumption. Such impairments were exacerbated when these mice were fed with a high‐fat diet. Upon 6‐hour cold exposure, RIP‐APPL2‐KO mice were cold sensitive due to the defective lipolytic and thermogenic responses in WAT but not BAT. During chronic cold acclimation, browning program was almost absent in subcutaneous WAT (sWAT) of RIP‐APPL2‐KO mice, whereas no obvious change appeared in their BAT. The impaired browning in RIP‐APPL2‐KO mice was due to decreased neuronal activation in raphe pallidus and subsequent diminished sympathetic outflow to sWAT. Peripheral treatment of CL316243 (β3 adrenergic receptor agonist), which bypassed SNS activation, could reverse the impaired browning phenotype in sWAT of RIP‐APPL2‐KO mice, indicating that the defect does not lie in sWAT but in hypothalamus. Likewise, adeno‐associated virus (AAV)‐mediated specific knockout of APPL2 in ventromedial hypothalamus recapitulated the defective browning phenotypes of RIP‐APPL2‐KO mice.ConclusionOur study uncovers a novel role of ventromedial hypothalamic RIP neurons in maintaining energy homeostasis by controlling browning in sWAT with the involvement of the adaptor protein APPL2.Support or Funding InformationThis work was supported by Health and Medical Research Fund (HMRF 01231606 to KKY Cheng).