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. 2022 Jun 6;13:915139. doi: 10.3389/fendo.2022.915139

Figure 3.

Figure 3

(A) The role of BMAL1 in glucose metabolism. BMAL1 controls hepatic glucose metabolism and pancreatic β-cell insulin secretion. In skeletal muscle, muscle-specific loss of BMAL1 results in reduced glucose oxidation. In addition to the hormone regulation of global glucose homeostasis, BMAL1 participates in concrete glucose metabolism processes. BMAL1 restrains glycolysis levels, while activation of BMAL1 inhibits pyruvate dehydrogenase kinase (PDK), resulting in the disinhibition of the pyruvate dehydrogenase complex (PDC). Then PDC drives the conversion of pyruvate to acetyl-coenzyme A (acetyl-CoA) in mitochondria, thus increasing the TCA cycle, OXPHOS and ATP production. Loss-of function of BMAL1 leads to the disruption of the aforementioned process and cellular senescence. (B) The role of BMAL1 in lipid metabolism. In the liver, BMAL1 regulates lipid synthesis, fatty acid oxidation, lipolysis and lipid homeostasis. Hepatocyte BMAL1 is required for post-prandial de novo lipogenesis through insulin-mTORC2-AKT- ChREBP-lipogenesis. BMAL1 regulates fatty acid oxidation by activating the transcription of the PPARα gene by binding to the E-box within the gene promoter. BMAL1 also regulates homeostasis lipogenesis through CREBH. In white adipose tissue, BMAL1 regulates genes involved in lipogenesis such as SREBP-1a and REV-ERB α, resulting in the promotion of lipid synthesis and accumulation. BMAL1 regulates lipid storage through the expression of Adipoq, Retn, Nampt, AdipoR1 and AdipoR2. BMAL1 regulates lipolysis by directly and rhythmically binding to Eboxes in the promoters of Atgl and Hsl. In skeletal muscle, BMAL1 regulates oxidative capacity and fat oxidation activity through the regulation of Cacnas expression, followed by the NFAT axis. (C) The role of BMAL1 in amino acid metabolism. In muscle tissue, loss of function of BMAL1 is associated with protein catabolism. increased glucogenic amino acids (alanine, glutamine, glutamate, glycine, serine, threonine, methionine, proline, and aspartate) as well as BCAAs (leucine, isoleucine, and valine). In the liver, loss of BMAL1 leads to an increase in blood plasma amino acids, such as glutamine, glutamate, glycine, serine, proline, leucine, and valine. In SCN, loss of BMAL1 increases most neurotransmitter amino acid, such as excitatory (Aspartate, Glutamate) or inhibitory (Glycine) and precursors (Glutamine).