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. 2021 Sep 24;10(10):2532. doi: 10.3390/cells10102532

Figure 2.

Figure 2

Direct and indirect actions of GH in controlling hepatocyte carbohydrate and lipid metabolism in response to nutrient deprivation (fasting, food restriction, diabetes type (I), and nutrient excess (overnutrition, obesity, and diabetes type (II)). Left panel: In the context of nutrient deprivation, circulating insulin and IGF1 levels are reduced, while the GH level is increased. GH promotes white adipose tissue lipolysis, leading to an increase in circulating non-esterified fatty acids (NEFA) and glycerol that serve as substrates for hepatic gluconeogenesis, fatty acid (β) oxidation, and ketogenesis. The NEFA released from lipolysis impairs glucose uptake in the skeletal muscle, due to substrate competition. There is suggestive evidence that GH directly stimulates gluconeogenesis and plays a role in ATP generation to sustain gluconeogenesis. However, it should be noted that prolonged fasting leads to hepatic GH resistance. Therefore, these direct actions of GH on gluconeogenesis may be more relevant in normal diurnal cycles of feeding and fasting. Right panel: In the context of nutrient excess, obesity develops and can lead to skeletal muscle and WAT insulin resistance, linked to inflammation. This is associated with the development of hepatic insulin resistance and steatosis. In this context, circulating GH levels are reduced. Evidence collected from mouse models with the loss of hepatocyte GHR indicates the GHR is required to suppress steatosis by inhibiting glycolysis driven de novo lipogenesis (DNL). The exact mechanisms driving enhanced DNL after hepatocyte-specific loss of GH signaling remains to be determined and could include the following: (1) derepression of hepatic insulin signaling; (2) a reduction in gluconeogenesis shifting substrates toward DNL; and/or (3) regulating, yet to be determined, endpoints that alter glycolysis-driven DNL. Green lines (ending >) depict positive actions, and red lines (ending |) depict negative actions. Dotted lines (…) indicate reduced signaling due to impaired receptor signaling, while dashed lines (---) indicate reduced pathway activation due to a reduction in ligand.