AHNAK KO Mice are Protected from Diet-Induced Obesity but are Glucose Intolerant

Abstract

AHNAK is a 700 KD phosphoprotein primarily involved in calcium signaling in various cell types and regulating cytoskeletal organization and cell membrane architecture. AHNAK expression has also been associated with obesity. To investigate the role of AHNAK in regulating metabolic homeostasis, we studied whole body AHNAK knockout mice (KO) on either regular chow or high-fat diet (HFD). KO mice had a leaner phenotype and were resistant to high-fat diet-induced obesity (DIO), as reflected by a reduction in adipose tissue mass in conjunction with higher lean mass compared to wild-type controls (WT). However, KO mice exhibited higher fasting glucose levels, impaired glucose tolerance, and diminished serum insulin levels on either diet. Concomitantly, KO mice on HFD displayed defects in insulin signaling, as evident from reduced Akt phosphorylation and decreased cellular glucose transporter (Glut4) levels. Glucose intolerance and insulin resistance were also associated with changes in expression of genes regulating fat, glucose, and energy metabolism in adipose tissue and liver. Taken together, these data demonstrate that (a) AHNAK is involved in glucose homeostasis and weight balance (b) under normal feeding KO mice are insulin sensitive yet insulin deficient; and (c) AHNAK deletion protects against HFD-induced obesity, but not against HFD-induced insulin resistance and glucose intolerance in vivo.

Ahnak stimulates BMP2‐mediated adipocyte differentiation through Smad1 activation

“…Function of Ahnak in Adipogenesis Shin et al decreased PPARc expression in mice fed a high-fat diet markedly decreased adipose tissue mass and impaired adipogenesis (29,30). This phenotype is similar with Ahnak-deficient mice fed a high-fat diet (14). Thus, in this cascade, Ahnak induced BMP2-mediated adipocyte differentiation from MSCs and suppressed differentiation to other cell types such as chondrocytes and osteoblasts.…”

“…Two recent studies revealed that Ahnak‐deficient (Ahnak −/− ) mice have a strong resistance to high‐fat diet‐induced obesity and show a lean phenotype, resulting from reduction in adipose tissue mass . Because BMP2 signaling is related to adipocyte differentiation, we hypothesized that Ahnak is involved in adipocyte differentiation through the activation of BMP2‐mediated cell signaling.…”

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

“…BSCL2 is of interest, as it is a known candidate gene for the most severe lipodystrophy phenotype32. In blood rs7949030 was found to be an eQTL of HNRNPUL2-BSCL2 , AHNAK , LRRN4CL and INTS5 (refs 33, 34), while in skin and adipocytes it was found as an eQTL for EML3 (refs 30, 31, 35). …”

Development and Genome Sequencing of a Laboratory-Inbred Miniature Pig Facilitates Study of Human Diabetic Disease

“…SVs identified influence genes involved in metabolic disorders. Three genes, AHNAK, ADGRF5/GPR116, and ATP10D, reported to regulate obesity (Ramdas et al, 2015), were affected by both deletion and duplication events within exonic regions (Table S21). Knocking out the AHNAK gene in mice results in protection from diet-induced obesity, ADGRF5/GPR116 affects insulin sensitivity via modulation of adipose function (Nie et al, 2012), and ATP10D is involved in endoplasmic reticulum-to-Golgi ceramide processing and regulation of obesity (Kengia et al, 2013).…”