Cell-autonomous adiposity through increased cell surface GLUT4 due to ankyrin-B deficiency

Abstract

Obesity typically is linked to caloric imbalance as a result of overnutrition. Here we propose a cell-autonomous mechanism for adiposity as a result of persistent cell surface glucose transporter type 4 (GLUT4) in adipocytes resulting from impaired function of ankyrin-B (AnkB) in coupling GLUT4 to clathrin-mediated endocytosis. Adipose tissue-specific AnkB-KO mice develop obesity and progressive pancreatic islet dysfunction with age or high-fat diet (HFD). AnkB-deficient adipocytes exhibit increased lipid accumulation associated with increased glucose uptake and impaired endocytosis of GLUT4. AnkB binds directly to GLUT4 and clathrin and promotes their association in adipocytes. AnkB variants that fail to restore normal lipid accumulation and GLUT4 localization in adipocytes are present in 1.3% of European Americans and 8.4% of African Americans, and are candidates to contribute to obesity susceptibility in humans.

A giant ankyrin-B mechanism for neuro-diversity/divergence through stochastic ectopic axon projections

“…However, the increasing application whole exome sequencing promises to open a new era of personalized molecular diagnosis. We predict that two distinct classifications within ANK2 patient variants will resolve: one where the mutation only affects exon 37 which would produce a neurological phenotype, and second where the mutation affects both the 220kDa ankyrin as well as the giant ankB which would have in addition long QT cardiac abnormalities and metabolic syndrome [9][10][11][12] . ANK2 variants found by exome sequencing can be functionally tested in our molecular replacement assay which evaluates axon branching (Fig.…”

“…ANK2 is a member of the ankyrin gene family that, together with their spectrin partners, is responsible for functional organization of vertebrate plasma membranes in a variety of physiological contexts 8 . ANK2 encodes 2 major ankyrin-B (ankB) polypeptides: one of 220 kDa that is broadly expressed and associated with cardiac arrhythmia 9,10 as well as age-dependent obesity 11,12 , and another of 440 kDa (giant ankB) that is expressed only in neurons and targets to axons (Extended Data Fig.1a) [13][14][15][16][17] . 220-kDa ankB functions in polarized transport of intracellular organelles as a PI3P adaptor that also binds to dynactin 17,18 .…”

Cargo hold and delivery: Ankyrins, spectrins, and their functional patterning of neurons

“…The PtdIns(3)P lipids binding site in the 220 kDa isoform of ankyrin‐B is conserved in other family members (Wang et al, ) and in multiple species, suggesting that other ankyrins might also interact with lipids on membranes through a similar motif. The UPA domain of ankyrin‐B contains a binding site for the dynactin subunit p62 (also known as dynactin‐4) required for the association of ankyrin‐B and the retrograde motor complex in neurons, skeletal muscle cells, embryonic fibroblasts, and adipocytes (Ayalon et al, ; Lorenzo et al, ; Lorenzo & Bennett, ; Qu et al, ). The ZU5 N ‐ZU5 C ‐UPA supermodule is followed by a death domain (DD).…”

“…In a departure from their canonical roles as static plasma membrane organizers, members of the ankyrin and spectrin families associate with molecular motors and organelles to facilitate intracellular transport in neurons and other cell types (Lorenzo et al, , , ; Lorenzo & Bennett, ; Muresan et al, ; Qu et al, ; Takeda et al, ). For example, the 220 kDa ankyrin‐B isoform couples the dynactin/dynein motor complex to multiple organelles to promote their retrograde axonal transport (Lorenzo et al, ).…”

ANK2 autism mutation targeting giant ankyrin-B promotes axon branching and ectopic connectivity

“…ANK2 encodes 2 major ankyrin-B (ankB) polypeptides, one of 220 kDa that is expressed in multiple tissues and the other of 440 kDa (referred to as giant ankB) that is expressed only in the nervous system (5–7). The 220-kDa ankB functions in polarized transport of intracellular organelles as a PI3P-binding adaptor for dynactin, and also promotes internalization of Glut4 (8–11). Mice lacking both ankB polypeptides die neonatally with loss of long axon tracts, including pyramidal tracts and the corpus callosum (9, 12).…”