Endocrine Abstracts

Introduction: Krüpel-like factor 4 (KLF4) is a zinc-finger-type transcription factor expressed in a range of tissues that plays multiple functions. KLF4 is expressed in neural stem cells and is critical to neuronal differentiation. Recent evidence suggests that KLF4 also plays an important role in the central regulation of energy balance. In vitro studies show that KLF4 is a transcriptional regulator of agouti–related protein (AgRP), essential to the hyperphagic response.

Description of methods/design: Sprague Dawley rats, WT and ob/ob mice. Stereotaxic microinjection of adenoviral and lentiviral expression vectors. Body composition, locomotor activity and indirect calorimetry. Leptin central pathway studies. Leptin sensitivity assays. Immunohistochemistry. Western blotting. Liver trygliceride content.

Results: We report that hypothalamic KLF4 represents a new transcription factor specifically modulating agouti-related protein (AgRP) expression in vivo. Hypothalamic KLF4 colocalises with AgRP neurons and is modulated by nutritional status and leptin. Over-expression of KLF4 in the hypothalamic arcuato nucleus (ARC) induces food intake and increases body weight through the specific stimulation of AgRP, as well as blunting leptin sensitivity in lean rats independent of forkhead box protein 01 (FoxO1). Down-regulation of KLF4 in the ARC inhibits fasting-induced food intake in both lean and diet-induced obese (DIO) rats. Silencing KLF4, however, does not, on its own, enhance peripheral leptin sensitivity in DIO rats.

Conclusion: i) Hypothalamic KLF4 is regulated by leptin through both STAT3 and PI3K signalling pathways. ii) KLF4 over-expression in the ARC is sufficient to increase food intake and to blunt the anorectic action of leptin in a FoxO1-independent manner. iii) Leptin fails to inhibit hypothalamic KLF4 expression in DIO rats, while KLF4 does not on its own regulate HFD-induced peripheral leptin resistance.

Disclosure: Ministerio de Economía y Competitividad (CD: BFU2011-29102; RN: RYC-2008-02219 and BFU2012-35255), Xunta de Galicia (ML: 10PXIB208164PR and 2012-CP070; RN: EM 2012/039 and 2012-CP069). European Community’s Seventh Framework Programme: CD, ML and RN.