Figure 3.

Model for stimulation of glucagon secretion by FAs and effects of glucagon signaling on hepatic lipid metabolism. Circulating FAs, primarily LCFAs, may stimulate glucagon secretion from pancreatic α-cells through various known and unknown mechanisms. This may involve FFAR1 and FFAR4 with subsequent increase in intracellular Ca²⁺ and cAMP. Likewise, β-oxidation in α-cells may result in the release of glucagon. Fatty acids may also inhibit somatostatin release from δ-cells through decreased intracellular cAMP via FFAR4 activation. The reduced somatostatin release results in decreased activation of several somatostatin receptors (SSTRs) on α-cells, which results in less inhibition of cAMP generation. FAs can also stimulate insulin secretion from β-cells through FFAR1 and FFAR4, and insulin may inhibit glucagon release through the insulin receptor (INSR) on α-cells. Once secreted, glucagon binds the hepatic GCGRs, stimulates β-oxidation, and inhibits de novo lipogenesis. GCGR signaling inhibits acetyl-CoA carboxylase (ACC) via protein kinase A (PKA) and AMP-activated protein kinase (AMPK), resulting in decreased malonyl-CoA formation. As a result, mitochondrial entry of FAs and β-oxidation are increased, while the availability of FAs for triglyceride synthesis and subsequent export is reduced. PLC, phospholipase C.