Abstract
Krüppel-like factor 4 (KLF4) is a zinc-finger-type transcription factor expressed in a range of tissues that plays multiple functions. We report that hypothalamic KLF4 represents a new transcription factor specifically modulating agouti-related protein (AgRP) expression in vivo. Hypothalamic KLF4 colocalizes with AgRP neurons and is modulated by nutritional status and leptin. Over-expression of KLF4 in the hypothalamic arcuate 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.
Highlights
Krüppel-like factor 4 (KLF4) is a zinc-finger-containing transcription factor that binds to GC-rich DNA with a consensus binding sequence of CACCC [1,2]
We first hypothesized that if KLF4 binds to a specific CACCC-box in the agouti-related protein (AgRP) promotor [8], hypothalamic KLF4 should be modulated by nutritional status and leptin
Over-expression of KLF4 in the hypothalamic arcuate nucleus increases food intake and body weight through stimulation of AgRP Since KLF4 is located in AgRP neurons and is regulated by nutritional status and leptin, we investigated whether specific overexpression of KLF4 in the ARC would be sufficient to affect food intake and body weight
Summary
Krüppel-like factor 4 (KLF4) is a zinc-finger-containing transcription factor that binds to GC-rich DNA with a consensus binding sequence of CACCC [1,2]. AgRP neurons are located within the hypothalamic arcuate nucleus (ARC), which contains two neural populations that are crucial to the regulation of food intake In one of these populations, neurons coexpress neuropeptide Y (NPY) and AgRP, both potent stimulators of food intake, while an adjacent set of ARC neurons co-express proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), both of which suppress food intake [10]. The cells of both populations respond to signals pertaining to long- and shortterm energy status in the animal. Down-regulation of KLF4 in the ARC of HFD-fed rats
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