Palmitic Acid Hydroxystearic Acids Activate GPR40, Which Is Involved in Their Beneficial Effects on Glucose Homeostasis

Abstract

Palmitic acid hydroxystearic acids (PAHSAs) are endogenous lipids with anti-diabetic and anti-inflammatory effects. PAHSA levels are reduced in serum and adipose tissue of insulin-resistant people and high-fat diet (HFD)-fed mice. Here, we investigated whether chronic PAHSA treatment enhances insulin sensitivity and which receptors mediate PAHSA effects. Chronic PAHSA administration in chow- and HFD-fed mice raises serum and tissue PAHSA levels ∼1.4- to 3-fold. This improves insulin sensitivity and glucose tolerance without altering body weight. PAHSA administration in chow-fed, but not HFD-fed, mice augments insulin and glucagon-like peptide (GLP-1) secretion. PAHSAs are selective agonists for GPR40, increasing Ca flux, but not intracellular cyclic AMP. Blocking GPR40 reverses improvements in glucose tolerance and insulin sensitivity in PAHSA-treated chow- and HFD-fed mice and directly inhibits PAHSA augmentation of glucose-stimulated insulin secretion in human islets. In contrast, GLP-1 receptor blockade in PAHSA-treated chow-fed mice reduces PAHSA effects on glucose tolerance, but not on insulin sensitivity. Thus, PAHSAs activate GPR40, which is involved in their beneficial metabolic effects.

Methodological Issues in Studying PAHSA Biology: Masking PAHSA Effects

“…So the data of Pflimlin et al in HFD-fed mice do not differ from our data. Our results indicate that the beneficial metabolic effects of PAHSAs in HFD mice result primarily from improved insulin sensitivity (Syed et al, 2018). …”

“…Ideally, if PAHSAs are beneficial, the effects would be present on more than one diet, but not necessarily with a single PAHSA dose in insulin-sensitive mice. Although we showed beneficial effects of constant PAHSA infusion by subcutaneous minipump for 9–13 days (Syed et al, 2018) or daily gavage for 12 days (unpublished data) in chow-fed mice, we have not published effects of a single dose of PAHSAs in young, lean chow-fed mice with normal glucose tolerance and insulin sensitivity. To that point, in the study by Pflimlin et al, there is no evidence of glucose intolerance in their vehicle-treated HFD mice, and data indicating insulin resistance are insufficient, consisting only of elevated insulin levels 4.5 hr after food removal with no statistical difference reported for insulin tolerance test (ITT) (Figure 3B in Pflimlin et al, 2018).…”

“…To that point, in the study by Pflimlin et al, there is no evidence of glucose intolerance in their vehicle-treated HFD mice, and data indicating insulin resistance are insufficient, consisting only of elevated insulin levels 4.5 hr after food removal with no statistical difference reported for insulin tolerance test (ITT) (Figure 3B in Pflimlin et al, 2018). In fact, Figure 2B in Pflimlin et al indicates that glucose tolerance is not different between vehicle-treated LFD and HFD mice using the hydrogenated vegetable diet, in contrast to the glucose intolerance and insulin resistance seen with this same HFD in Yore et al (2014) and Syed et al (2018). In addition, glucose tolerance in mice on the high-fat coconut oil diet (Figure S2A in Pflimlin et al, 2018) is not different from that in mice on the corresponding LFD.…”

“…However, it is worth noting that we did not report an effect of PAHSAs on GLP-1 or insulin secretion in HFD-fed mice with either acute or chronic treatments. We reported the effect of a single PAHSA dose on GLP-1 and insulin secretion only in aged, glucose-intolerant chow-fed mice (Yore et al, 2014) and the effect of continuous PAHSA infusion by mini pump in ~4-month-old chow-fed mice (Syed et al, 2018). So the data of Pflimlin et al in HFD-fed mice do not differ from our data.…”

“…Levels of multiple PAHSA isomers are reduced in serum and subcutaneous adipose tissue of insulin-resistant mice and humans, and serum PAHSA levels correlate highly with insulin sensitivity in humans (Yore et al, 2014). A single oral dose of 5-PAHSA or 9-PAHSA improves glucose tolerance in aged, glucose-intolerant chow-fed and high-fat diet (HFD)-fed mice (Yore et al, 2014), whereas chronic subcutaneous PAHSA treatment improves both insulin sensitivity and glucose tolerance in chow-fed and HFD-fed mice (Syed et al, 2018). The anti-inflammatory effects of PAHSAs are seen in mouse models of insulin resistance (Syed et al, 2018; Vijayakumar et al, 2017; Yore et al, 2014), colitis (Lee et al, 2016), and type 1 diabetes (Syed et al, 2017).…”