Abstract
Autophagy, a highly conserved intracellular self-digestion process, plays an integral role in maintaining cellular homeostasis. Although emerging evidence indicate that the endocrine system regulates autophagy in mammals, there is still a scarcity of information on autophagy in avian (non-mammalian) species. Here, we show that intracerebroventricular administration of leptin reduces feed intake, modulates the expression of feeding-related hypothalamic neuropeptides, activates leptin receptor and signal transducer and activator of transcription (Ob-Rb/STAT) pathway, and significantly increases the expression of autophagy-related proteins (Atg3, Atg5, Atg7, beclin1, and LC3B) in chicken hypothalamus, liver, and muscle. Similarly, leptin treatment activates Ob-Rb/STAT pathway and increased the expression of autophagy-related markers in chicken hypothalamic organotypic cultures, muscle (QM7) and hepatocyte (Sim-CEL) cell cultures as well as in Chinese Hamster Ovary (CHO-K1) cells-overexpressing chicken Ob-Rb and STAT3. To define the downstream mediator(s) of leptin's effects on autophagy, we determined the role of the master energy sensor AMP-activated protein kinase (AMPK). Leptin treatment significantly increased the phosphorylated levels of AMPKα1/2 at Thr172 site in chicken hypothalamus and liver, but not in muscle. Likewise, AMPKα1/2 was activated by leptin in chicken hypothalamic organotypic culture and Sim-CEL, but not in QM7 cells. Blocking AMPK activity by compound C reverses the autophagy-inducing effect of leptin. Together, these findings indicate that AMPK mediates the effect of leptin on chicken autophagy in a tissue-specific manner.
Highlights
Autophagy is a highly conserved intracellular self-digestion process by which cells degrade and recycle their own constituents, including damaged organelles, within lysosomes (Levine and Klionsky, 2004; Levine and Kroemer, 2008)
The hypothalamic expression of neuropeptide Y (NPY), corticotropin releasing hormone (CRH), orexin (ORX) and its related receptors ORXR1 and ORXR2 was significantly upregulated in leptin-treated compared to the control group at 180 min post treatment (Figure 1B)
Leptin is an adipocytokine that is primarily produced by mammalian white adipocytes (Zhang et al, 1994), it is expressed in several other tissues including the stomach (Bado et al, 1998), lungs (Vernooy et al, 2009), placenta (Hoggard et al, 1997a), and brain (Wiesner et al, 1999)
Summary
Autophagy is a highly conserved intracellular self-digestion process by which cells degrade and recycle their own constituents, including damaged organelles, within lysosomes (Levine and Klionsky, 2004; Levine and Kroemer, 2008). Unlike the micro-autophagy which is mediated by direct lysosome engulfment of the cytosolic cargo via invagination in their limiting membrane, macro-autophagy (hereafter autophagy) refers to the sequestration within a doublemembrane structures called autophagosome which enclose cellular material and fuse with lysosomes (Mortimore et al, 1988; Todde et al, 2009). The outer autophagosomal membrane fuses with that of the lysosome in reaction involving several proteins such as ESCRT (Lee et al, 2007), SNAREs (Nair et al, 2011; Itakura et al, 2012), Rab (Gutierrez et al, 2004; Jäger et al, 2004), and Vps (Liang et al, 2008) leading, in turn, to the releases of autophagic body into lysosomal lumen for hydrolase degradation and recycling of macromolecular components for cellular use
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