BBS-Induced Ciliary Defect Enhances Adipogenesis, Causing Paradoxical Higher-Insulin Sensitivity, Glucose Usage, and Decreased Inflammatory Response

Marion, Vincent; Mockel, Anaïs; Melo, Charlie De; Obringer, Cathy; Claussmann, Aurélie; Simon, Alban; Messaddeq, Nadia; Durand, Myriam; Dupuis, Luc; Loeffler, Jean‐Philippe; King, Peter; Mutter-Schmidt, Catherine; Petrovsky, Nikolai; Stoetzel, Corinne; Dollfus, Hélène

doi:10.1016/j.cmet.2012.08.005

Cited by 75 publications

(106 citation statements)

References 66 publications

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“…The present data suggest that a single PO challenge promotes pathways of LPSand TLR4-mediated inflammation and cytotoxicity, which are buffered by the activation of NF-κB, which in turn contributes to insulin resistance. This study also found altered regulation of other putative cytoprotective mechanisms including the phospholipase C4 pathway, which is important for hepatic regeneration (54), and PPARα, which serves as both a canonical pathway and an upstream regulator protecting against NAFLD progression (29).…”

Section: Figure 2 Time Courses Of Circulating Metabolites and Hormonmentioning

confidence: 84%

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

Hernández¹,

Kahl²,

Seelig³

et al. 2017

Journal of Clinical Investigation

152

130

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H and ex vivo2 H magnetic resonance spectroscopy before and during hyperinsulinemiceuglycemic clamps with isotope dilution. Mice underwent identical clamp procedures and hepatic transcriptome analyses.RESULTS. PO administration decreased whole-body, hepatic, and adipose tissue insulin sensitivity by 25%, 15%, and 34%, respectively. Hepatic triglyceride and ATP content rose by 35% and 16%, respectively. Hepatic gluconeogenesis increased by 70%, and net glycogenolysis declined by 20%. Mouse transcriptomics revealed that PO differentially regulates predicted upstream regulators and pathways, including LPS, members of the TLR and PPAR families, NF-κB, and TNF-related weak inducer of apoptosis (TWEAK). CONCLUSION.Saturated fat ingestion rapidly increases hepatic lipid storage, energy metabolism, and insulin resistance. This is accompanied by regulation of hepatic gene expression and signaling that may contribute to development of NAFLD. PO results in increased circulating TG, glucagon, and incretins. After PO administration, TG in plasma rose by 59% (area under the time curve [AUC], P < 0.001) and by 156% in chylomicrons (AUC, P = 0.009) (Figure 2A). The AUC for plasma free fatty acids (FFA) ( Figure 2B) and insulin concentrations ( Figure 2C) was unchanged, while the AUC for plasma C-peptide was 28% higher after PO ingestion versus VCL (P < 0.005, Figure 2D). Of note, FFA were increased at 300, 420, and 480 minutes. Blood glucose levels were not different between PO-and VCL-treated groups ( Figure 2E). Plasma glucagon rose by 41% (AUC, P < 0.0001) only after PO ingestion ( Figure 2F). Also, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels were markedly increased and remained elevated after PO ingestion (both P < 0.005) (Supplemental Figure 2; supplemental material available online with this article; https://doi.org/10.1172/ JCI89444DS1). Circulating levels of TNF-α, IL-6, fetuin-A, chemerin, omentin, and cortisol were not different between PO and VCL groups (P > 0.5 for all) (Supplemental Table 1). REGISTRATION. The Journal of Clinical Investigation C L I N I C A L M E D I C I N EPO induces insulin resistance at whole-body, liver, and adipose tissue levels. Insulin sensitivity was measured using hyperinsulinemic-euglycemic clamp tests in healthy humans. Steady state was reached (Supplemental Figure 1), and pertinent parameters were analyzed during this time. PO ingestion reduced WBIS by 25% compared with VCL treatment (P = 0.0005, Figure 3A). Furthermore, after PO, volunteers also showed a decrease of 22% (P = 0.002) in the rate of glucose disappearance (Rd), mostly due to a 33% (P = 0.01) reduction in glucose oxidation (GOX), while the rate of nonoxidative glucose disposal remained unchanged

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Section: Figure 2 Time Courses Of Circulating Metabolites and Hormonmentioning

confidence: 84%

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

Hernández¹,

Kahl²,

Seelig³

et al. 2017

Journal of Clinical Investigation

152

130

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“…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].…”

Section: Adipogenesis Defects In the Etiology Of The Bbs Related Obesitymentioning

confidence: 99%

“…However, a study comparing BBS patients with BMI-matched controls showed that the former present better glucose tolerance, thus hinting at potentially important differences between BBS-related and common obesity [138]. Marion and colleagues showed that knockdown of BBS12 in hMSCs results in increased adipogenesis that is accompanied by increased expression of the insulin receptor (IR) and GLUT4, increased localization of GLUT4 to the plasma membrane, and overall increased glucose absorption, and Bbs12 À/À animals present increased insulin sensitivity, improved glucose metabolism and reduced inflammation [136]. Importantly, since adipocytes secrete leptin in response to insulin and glucose, the increased glucose absorption and the overall increased adipogenesis are likely to contribute to the hyperleptinemia that characterize BBS [21,138].…”

Section: Adipogenesis Defects In the Etiology Of The Bbs Related Obesitymentioning

confidence: 99%

Bardet–Biedl syndrome: Is it only cilia dysfunction?

et al. 2015

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a b s t r a c tBardet-Biedl syndrome (BBS) is a genetically heterogeneous, pleiotropic disorder, characterized by both congenital and late onset defects. From the analysis of the mutational burden in patients to the functional characterization of the BBS proteins, this syndrome has become a model for both understanding oligogenic patterns of inheritance and the biology of a particular cellular organelle: the primary cilium. Here we briefly review the genetics of BBS to then focus on the function of the BBS proteins, not only in the context of the cilium but also highlighting potential extra-ciliary roles that could be relevant to the etiology of the disorder. Finally, we provide an overview of how the study of this rare syndrome has contributed to the understanding of cilia biology and how this knowledge has informed on the cellular basis of different clinical manifestations that characterize BBS and the ciliopathies.

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“…In addition, the effect on the level of hyperplasia and hypertrophy may differ per gene. By studying Bbs12-knockout mice (144) , it was observed that those mice had a higher number of small-sized to normal-sized adipocytes between hypertrophic cells than the wild-type mice. As small adipocytes are supposed to have a more healthy metabolic activity (152) , this was seen as a possible explanation for the low risk of BBS12 patients to develop type 2 diabetes, whereas in Alström syndrome early-onset type 2 diabetes is common (20,153) .…”

Section: A Primary Cilium For Adipogenesismentioning

confidence: 99%

“…Ciliary proteins may influence either one or both of these forces, and have therefore been referred to as gatekeepers of adipocyte differentiation (144) . Marion et al (144) showed that the reduced expression of the BBS12 gene in mesenchymal stem cells down-regulated the anti-adipogenic pathways but promoted the pro-adipogenic factors. On the other hand, a decrease in Alms1, Ift88 or Kif3a expression inhibits cilium formation, as well as also adipocyte differentiation in mouse 3T3-L1 cells (145,146) .…”

Section: A Primary Cilium For Adipogenesismentioning

confidence: 99%

The cilium: a cellular antenna with an influence on obesity risk

et al. 2016

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Primary cilia are organelles that are present on many different cell types, either transiently or permanently. They play a crucial role in receiving signals from the environment and passing these signals to other parts of the cell. In that way, they are involved in diverse processes such as adipocyte differentiation and olfactory sensation. Mutations in genes coding for ciliary proteins often have pleiotropic effects and lead to clinical conditions, ciliopathies, with multiple symptoms. In this study, we reviewed observations from ciliopathies with obesity as one of the symptoms. It shows that variation in cilia-related genes is itself not a major cause of obesity in the population but may be a part of the multifactorial aetiology of this complex condition. Both common polymorphisms and rare deleterious variants may contribute to the obesity risk. Genotype-phenotype relationships have been noticed. Among the ciliary genes, obesity differs with regard to severity and age of onset, which may relate to the influence of each gene on the balance between pro-and anti-adipogenic processes. Analysis of the function and location of the proteins encoded by these ciliary genes suggests that obesity is more linked to activities at the basal area of the cilium, including initiation of the intraflagellar transport, but less to the intraflagellar transport itself. Regarding the role of cilia, three possible mechanistic processes underlying obesity are described: adipogenesis, neuronal food intake regulation and food odour perception.

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BBS-Induced Ciliary Defect Enhances Adipogenesis, Causing Paradoxical Higher-Insulin Sensitivity, Glucose Usage, and Decreased Inflammatory Response

Cited by 75 publications

References 66 publications

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

Bardet–Biedl syndrome: Is it only cilia dysfunction?

The cilium: a cellular antenna with an influence on obesity risk

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