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    • Whereas allostery in the cell is relatively

    2022-11-24

    Whereas allostery in the β cell is relatively understudied, significant progress has been made in understanding the physiology and mechanistic biology of how AMPK and its upstream kinases govern β cell function. LKB1 phosphorylates AMPKα at Thr172 [21], and loss of LKB1 in β cells abolishes phosphorylation of Thr172 and of AMPK target proteins, demonstrating that LKB1 is a key regulator of AMPK in this setting (see below) 22, 23, 24. Of the alternative AMPKα kinases reported in other systems [e.g., transforming growth factor β-activated kinase 1 (TAK1) and Ca2+/calmodulin-dependent kinase kinase 2 (CAMKK2)], only CAMKK2 has been implicated in AMPK regulation in β cells 25, 26, 27, 28 (see below). Given that LKB1 is thought to be constitutively active, stimuli must modulate AMPK activity through changes in AMP/ADP binding or by inhibiting an AMPK phosphatase. In the β cell, this phosphatase may be protein phosphatase 1 (PP1), because silencing the R6 regulatory subunit of PP1 in MIN6 cells led to persistent AMPK phosphorylation in high glucose conditions and inhibited GSIS [29]. In several settings, including MIN6 cells, Ser485/Ser491 of the AMPKα1 and α2 subunits are phosphorylated by Akt, protein kinase A (PKA), or by autophosphorylation [30]. This phosphorylation correlated with AMPK inhibition (reviewed in [5]); however, a cognate kinase for Ser485 in the β cell is unknown.
    Targets of AMPK in the β Cell We previously reviewed this aspect of AMPK biology [6], and this is another area where the field often borrows from other systems. Identifying β cell-specific targets of AMPK remains a significant challenge. Consistent with its role as a central regulator of energy status, activated AMPK in the β cell phosphorylates enzymes, transporters, and transcription factors involved in glucose (GLUTs and glycogen synthase), fatty BMS-345541 (ACC1 and fatty acid synthase) and cholesterol (HMG-CoA reductase and SREBP) metabolism 31, 32, 33, 34, 35. Given that ACC1 catalyzes the rate-limiting step in fatty acid biosynthesis and its phosphorylation by AMPK slows lipid generation, targeting AMPK and/or ACC1 has been proposed as a strategy for treating obesity and insulin resistance. In the β cell, chronic pharmacological inactivation or silencing of ACC1 inhibits GSIS and associated metabolic events [36]; conversely, activation of ACC1 correlates with enhanced GSIS in cells lacking LKB1 [37] (see below). By directly targeting the transcriptional regulators SREBP, Foxo1a, and HNF4α, AMPK influences gene expression programs that govern fatty acid, cholesterol, and insulin synthesis, as well as apoptosis 38, 39, 40. Once activated by limited glucose and amino acids, AMPK also inhibits mTOR and protein synthesis, which is in part mediated by the AMPK target TSC2 41, 42, 43. Early efforts to identify additional β cell-specific targets of AMPK are largely limited to insulinoma cell lines [16]. Considering the functional discordance in glucose metabolism and glucose kinase(s) expression between cell lines and intact islets (reviewed previously in [6]), one might reasonably assume that AMPK targets relevant to nutrient sensing and survival may be unique to the islet. Despite significant technical challenges, discovery approaches using rodent and human islets are now needed (Box 1).
    The LKB1-AMPK Pathway and the β Cell
    GSIS: Enter the SIKs and SAD-A The first evidence that LKB1 controls additional cell biological parameters in the β cell came from the observation that the AMPK family member MARK2 was responsible for LKB1-mediated regulation of nuclear positioning in the β cell 22, 23. This pointed to a need to assign individual downstream AMPK family kinases to the specific LKB1-dependent phenotypes (Figure 3). Based on the relatively conserved consensus target phosphorylation site for the AMPK family members as the sole criterion 55, 56, 57, one might anticipate significant overlap in target proteins for the 14 members of the AMPK family, yet recently SIK1 and SIK2 and synapses of amphids defective-A (SAD-A) have taken center stage as novel regulators of distinct aspects of β cell biology (Figure 4).