Research Paper Volume 6, Issue 12 pp 1019—1032

Figure 7. Schematic diagram of GHS-R mediated thermogenic regulation in brown adipocytes.

Our data suggest that ghrelin signaling may regulate thermogenesis in BAT via the following 4 independent and interconnected signaling pathways: 1) Ablation of GHS-R stimulates SNS-mediated NE release, which in turn induces β3-AR expression, subsequently activating thermogenic signaling cascades in BAT. This involves activation of thermogenic signaling pathway PKA-CREB-UCP1 and lipolytic pathway PKA-HSL-UCP1. 2) Ablation of GHS-R enhances insulin signaling in BAT, which improves insulin sensitivity of BAT and activates key thermogenic regulator PKA. 3) Ablation of GHS-R enhances AMPK activity in BAT, which increases DNA and protein synthesis of mitochondria, thus increasing mitochondrial biogenesis. 4) Ablation of GHS-R augments mitochondrial dynamics, enhancing both mitochondrial fission and fussion; this restores mitochondrial architecture and improves mitochondrial homeostasis. Improved mitochondrial homeostasis enhances the sensitivity of mitochondria to FFA to further promote mitochondrial uncoupling. Collectively, GHS-R ablation increases thermogenesis in BAT by activating thermogenic signaling, sensitizing insulin signaling, increasing mitochondrial biogenesis, and enhancing mitochondrial dynamics.