Knockdown of the Alström syndrome-associated gene Alms1 in 3T3-L1 preadipocytes impairs adipogenesis but has no effect on cell-autonomous insulin action

Abstract

Alström syndrome is a rare genetic syndrome associated with early-onset obesity, severe insulin resistance (IR) that is disproportionate to the degree of adiposity and premature diabetes. The ALMS1 gene, which is mutated in Alström syndrome, encodes a giant 460 kDa centrosome-and basal body-associated protein. Its function is unknown, although roles in primary cilia formation and function, intracellular organelle trafficking and, most recently, adipocyte differentiation have been mooted. We now test the hypothesis that the severe IR and dyslipidaemia in Alström syndrome are accounted for by a partial defect in adipogenesis and/or insulin action in mature adipocytes, leading to relative failure of adipose tissue to discharge its role in metabolic homeostasis. Stable knockdown of Alms1 expression by 480% in 3T3-L1 preadipocytes was associated with impairment of lipid accumulation and at least a twofold reduction in adipocyte gene expression following hormonal induction of adipogenesis. This was accompanied by a commensurate defect in insulin-stimulated glucose uptake. Proximal signalling events in response to insulin were unaffected. These results suggest that partial impairment of adipogenesis in Alström syndrome may contribute to the severity of the associated metabolic phenotype, whereas the ability of insulin to stimulate glucose uptake into adipocytes is grossly unimpaired.

Metabolic Regulation and Energy Homeostasis through the Primary Cilium

“…Two days after such treatment, proadipogenic peroxisome proliferator-activated receptor γ (PPARγ) was detected in BBS10 and BBS12-depleted preadipocytes, suggesting that a functional cilium/basal body can negatively regulate adipogenesis. These results are in contrast with studies showing a down-regulation of PPARγ suppression of Alms1 and IFT proteins in transformed 3T3-L1 mouse preadipocytes(Huang-Doran and Semple, 2010). However, given that human preadipocytes can proceed to terminal differentiation without post-confluence mitosis, differences in PPARγ responsiveness may be attributed to cell line-specific variables.…”

The primary cilium undergoes dynamic size modifications during adipocyte differentiation of human adipose stem cells

“…Marion et al showed that depletion of BBS12 decreases the ratio of cilium-positive cells and increases adipocyte differentiation [5]. On the other hand, affecting the primary cilium through a decrease in Alms [29], IFT88 or Kif-3A [30,31] expression inhibit adipocyte differentiation. These observations suggest that the primary cilium controls several steps of adipogenesis and cannot be considered only as a "switch" that triggers or inhibits adipocyte differentiation.…”

Bardet–Biedl syndrome: Is it only cilia dysfunction?

“…However, the effect on adipogenesis varies depending on the specific ciliary protein being affected. In contrast to BBS10 and BBS12, knockdown of ALMS1 (mutated in ALMS) in 3T3-L1 inhibited adipogenesis [135]. Depletion of the ciliary proteins Pkd1 and BBS12 also resulted in enhanced adipogenesis while inhibition of the IFT anterograde molecular motor Kif3a impaired adipocyte differentiation [136,137].…”