Genetic loss of AMPK-glycogen binding destabilises AMPK and disrupts metabolism

Hoffman, Nolan J.; Whitfield, Jamie; Janzen, Natalie R.; Belhaj, Mehdi R.; Galić, Sandra; Murray‐Segal, Lisa; Smiles, William J.; Ling, Naomi X.Y.; Dite, Toby A.; Scott, John W.; Oakhill, Jonathan S.; Brink, Robert; Kemp, Bruce E.; Hawley, John A.

doi:10.1016/j.molmet.2020.101048

Cited by 26 publications

(28 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AMPK b subunits contain an N terminus myristoylation site as well as a conserved carbohydrate binding module (CBM) that facilitates interactions with glycogen and an ag binding domain at the C terminus. Recent work has assessed the physiologic implications of AMPKb subunit CBM glycogen binding (Hoffman et al, 2020). These studies indicate a role for glycogen binding in stabilizing AMPK complex formation, AMPK activation, and lipid metabolism across multiple tissues.…”

Section: The Ampk Heterotrimeric Complex and Its Functional Implicationsmentioning

confidence: 99%

AMPK: restoring metabolic homeostasis over space and time

2021

View full text Add to dashboard Cite

The evolution of AMPK and its homologs enabled exquisite responsivity and control of cellular energetic homeostasis. Recent work has been critical in establishing the mechanisms that determine AMPK activity, novel targets of AMPK action, and the distribution of AMPK-mediated control networks across the cellular landscape. The role of AMPK as a hub of metabolic control has led to intense interest in pharmacologic activation as a therapeutic avenue for a number of disease states, including obesity, diabetes, and cancer. As such, critical work on the compartmentalization of AMPK, its downstream targets, and the systems it influences has progressed in recent years. The variegated distribution of AMPK-mediated control of metabolic homeostasis has revealed key insights into AMPK in normal biology and future directions for AMPK-based therapeutic strategies. ll

show abstract

Section: The Ampk Heterotrimeric Complex and Its Functional Implicationsmentioning

confidence: 99%

AMPK: restoring metabolic homeostasis over space and time

2021

View full text Add to dashboard Cite

show abstract

“…We previously generated two isoform-specific AMPK β knock-in (KI) mouse models in which tryptophan residues critical for AMPK-glycogen binding were mutated in either the β1 (W100A) or β2 (W98A) subunit isoform [14]. We demonstrated that mice with a KI mutation to chronically disrupt glycogen-binding capacity in a single AMPK β subunit isoform predominately expressed in liver or skeletal muscle displayed reduced total AMPK content and kinase activity, which was associated with increased fat content in liver and skeletal muscle of β1 W100A and β2 W98A KI mice, respectively [14]. Additionally, β2 W98A KI mice displayed increased whole-body fat mass and impaired glucose handling [14].…”

Section: Introductionmentioning

confidence: 99%

Mice with Whole-Body Disruption of AMPK-Glycogen Binding Have Increased Adiposity, Reduced Fat Oxidation and Altered Tissue Glycogen Dynamics

Janzen

Whitfield

Murray‐Segal

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

The AMP-activated protein kinase (AMPK), a central regulator of cellular energy balance and metabolism, binds glycogen via its β subunit. However, the physiological effects of disrupting AMPK-glycogen interactions remain incompletely understood. To chronically disrupt AMPK-glycogen binding, AMPK β double knock-in (DKI) mice were generated with mutations in residues critical for glycogen binding in both the β1 (W100A) and β2 (W98A) subunit isoforms. We examined the effects of this DKI mutation on whole-body substrate utilization, glucose homeostasis, and tissue glycogen dynamics. Body composition, metabolic caging, glucose and insulin tolerance, serum hormone and lipid profiles, and tissue glycogen and protein content were analyzed in chow-fed male DKI and age-matched wild-type (WT) mice. DKI mice displayed increased whole-body fat mass and glucose intolerance associated with reduced fat oxidation relative to WT. DKI mice had reduced liver glycogen content in the fed state concomitant with increased utilization and no repletion of skeletal muscle glycogen in response to fasting and refeeding, respectively, despite similar glycogen-associated protein content relative to WT. DKI liver and skeletal muscle displayed reductions in AMPK protein content versus WT. These findings identify phenotypic effects of the AMPK DKI mutation on whole-body metabolism and tissue AMPK content and glycogen dynamics.

show abstract

“…The more traditional function of the CBM is to target AMPK to glycogen, an interaction we recently showed is critical for glucose handling and maximal exercise capacity [ 108 ]. The observed phenotype in this study was accompanied by a loss of total AMPK protein levels (~50–60% reduction), suggesting that the AMPK-glycogen interaction is important to stabilise certain pools of AMPK.…”

Section: Regulation By Phosphorylationmentioning

confidence: 99%

Post-Translational Modifications of the Energy Guardian AMP-Activated Protein Kinase

Ovens

Scott

Langendorf

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Physical exercise elicits physiological metabolic perturbations such as energetic and oxidative stress; however, a diverse range of cellular processes are stimulated in response to combat these challenges and maintain cellular energy homeostasis. AMP-activated protein kinase (AMPK) is a highly conserved enzyme that acts as a metabolic fuel sensor and is central to this adaptive response to exercise. The complexity of AMPK’s role in modulating a range of cellular signalling cascades is well documented, yet aside from its well-characterised regulation by activation loop phosphorylation, AMPK is further subject to a multitude of additional regulatory stimuli. Therefore, in this review we comprehensively outline current knowledge around the post-translational modifications of AMPK, including novel phosphorylation sites, as well as underappreciated roles for ubiquitination, sumoylation, acetylation, methylation and oxidation. We provide insight into the physiological ramifications of these AMPK modifications, which not only affect its activity, but also subcellular localisation, nutrient interactions and protein stability. Lastly, we highlight the current knowledge gaps in this area of AMPK research and provide perspectives on how the field can apply greater rigour to the characterisation of novel AMPK regulatory modifications.

show abstract

Genetic loss of AMPK-glycogen binding destabilises AMPK and disrupts metabolism

Cited by 26 publications

References 46 publications

AMPK: restoring metabolic homeostasis over space and time

AMPK: restoring metabolic homeostasis over space and time

Mice with Whole-Body Disruption of AMPK-Glycogen Binding Have Increased Adiposity, Reduced Fat Oxidation and Altered Tissue Glycogen Dynamics

Post-Translational Modifications of the Energy Guardian AMP-Activated Protein Kinase

Contact Info

Product

Resources

About