Rebuttal from Scott A. Summers and Bret H. Goodpaster
Year: 2016
Type: article
Abstract: Peterson and Jurczak identified two lines of evidence to question roles for ceramides in insulin resistance. The first relates to discordance between lipidomic profiling studies. Though we highlighted positive associations between muscle and liver ceramides with insulin resistance, the finding is not universal. As tissues are unlikely to rely on a single mechanism to gauge nutrient status, interpreting such differences between clinical cohorts is difficult. Infusion of unsaturated fats, for example, antagonizes insulin action through a ceramide-independent mechanism (Holland et al. 2007), but the artificial system does not faithfully mimic insulin resistance associated with obesity (Dube et al. 2014). Static quantifications of a few molecules from the sphingolipidome, particularly those using techniques that don't distinguish ceramide species, are unlikely to capture the dynamic changes that are occurring in vivo. Consideration of ceramide turnover, the timing of tissue collection vs. insulin sensitivity determination, the sampling site (muscle fibre type, subcellular locale, etc.), the size of the cohort, and the ceramide acylation pattern is critical when interpreting such work. Of note, since these CrossTalk articles were submitted, Luukkonen et al. (2016) published one of the largest profiling studies to date, finding that ‘saturated’ ceramides correlated with insulin resistance, independent of steatosis, in human liver. The second argument relates to the fact that insulin resistant patients sometimes display downregulation of IRS1 (Copps & White, 2012), a signalling step that is unaffected by ceramides (Stratford et al. 2004). Defective signalling to IRS1 is more likely to be a compensatory adaptation to prolonged insulin resistance that a causal factor in disease pathology. Proximal signalling events have such heightened occupancy/activation that partial inhibition rarely impacts downstream events in a linear fashion. Hoehn and colleagues used a PDGF transgene expression to circumvent the requirement for IRS1 in hormonal glucose disposal, demonstrating that diet-induced defects in muscle glucose uptake were independent of IRS1 (Hoehn et al. 2008). Moreover, inhibition of IRS1 in isolated muscle using knockdown (Cleasby et al. 2007) or by incubating with phorbol esters (i.e. to mimic diacylglycerol accumulation in obesity) (Lin et al. 2001) impairs insulin signalling to IRS1 without altering glucose uptake. Whether or not the ceramide action on Akt accounts for its ability to modulate glucose disposal (JeBailey et al. 2007), physiologically relevant increases in muscle ceramides do inhibit glucose uptake (Holland et al. 2007). Measurement of the terminal effects of insulin on metabolism is a better metric of insulin sensitivity than the expression or phosphorylation of signalling intermediates. While we acknowledge the lack of consistency between correlational studies, interventional approaches that exclusively and selectively target genes in the ceramide pathway have unequivocally shown that ceramides are essential for saturated fat-induced insulin resistance in skeletal muscle. Moreover, such approaches invariably improve insulin sensitivity and glucose tolerance in rodent models of obesity. The preponderance of data thus far support the promise of ceramide reduction as an insulin sensitizing therapeutic approach. Readers are invited to give their views on this and the accompanying CrossTalk articles in this issue by submitting a brief (250 word) comment. Comments may be submitted up to 6 weeks after publication of the article, at which point the discussion will close and the CrossTalk authors will be invited to submit a ‘Last Word’. Please email your comment, including a title and a declaration of interest, to [email protected]. Comments will be moderated and accepted comments will be published online only as ‘supporting information’ to the original debate articles once discussion has closed. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Scott Summers is a shareholder of Centaurus Therapeutics, Inc. Both authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.
Source: The Journal of Physiology
DOI: 10.1113/jp272136
Authors: Scott A. Summers, Bret H. Goodpaster
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2298573437