Abstract
Signal transducers and activators of transcription (STATs) are critical components of cytokine signaling pathways. STAT5A and STAT5B (STAT5), the most promiscuous members of this family, are highly expressed in specific populations of hypothalamic neurons in regions known to mediate the actions of cytokines in the regulation of energy balance. To test the hypothesis that STAT5 signaling is essential to energy homeostasis, we used Cre-mediated recombination to delete the Stat5 locus in the CNS. Mutant males and females developed severe obesity with hyperphagia, impaired thermal regulation in response to cold, hyperleptinemia and insulin resistance. Furthermore, central administration of GM-CSF mediated the nuclear accumulation of STAT5 in hypothalamic neurons and reduced food intake in control but not in mutant mice. These results demonstrate that STAT5 mediates energy homeostasis in response to endogenous cytokines such as GM-CSF.
Highlights
The central nervous system modulates feeding and energy expenditure to maintain energy balance and metabolism within a precise homeostatic window
Relevant to the phenotype described in this study, we detected STAT5 in a limited number of cells within areas of the hypothalamus known to regulate feeding and energy balance (Figure 1A), including the arcuate nucleus (Arc), dorsomedial and ventromedial hypothalamic nuclei (DMH and VMH), and the lateral hypothalamic area (LHA), suggesting a potential role for Stat5 in energy homeostasis
While a large body of evidence has pointed towards a key role for hypothalamic STAT3 in the regulation of energy balance, the current results suggest an important role for STAT5 in the regulation of feeding and body fat stores in response to endogenous signals
Summary
The central nervous system modulates feeding and energy expenditure to maintain energy balance and metabolism within a precise homeostatic window. Cytokines mediate many of the physiologic cues that activate neuronal signaling in these regions to regulate energy balance. Ciliary neurotrophic factor (CNTF), the adipocytokine leptin, and granulocyte-macrophage colony-stimulating factor (GMCSF) and IL-6 regulate food intake and body weight via the activation of endogenous hypothalamic cytokine receptors that mediate signaling via the Janus kinase 2 (JAK2) and signal transducer and activator of transcription (STAT) pathways. Mouse genetics has demonstrated that STAT3 [2,3,4,5] is essential for the regulation of energy balance in response to leptin and other endogenous cytokines. Neural SOCS3, an inhibitor of JAK2 and a variety of STATs, blocks signaling by several cytokines and thereby increases feeding and body weight by attenuating cytokine signaling in the CNS [6]. GM-CSF-dependent proliferation of macrophages is dependent on the presence of STAT5A [9]
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