LRG1 is an adipokine that mediates obesity-induced hepatosteatosis and insulin resistance

LRG1: an emerging player in disease pathogenesis

“…Lrg1 also belongs to a cluster of genes upregulated in adipose tissue during late embryonic and early postnatal development, at the time when adipocytes start accumulating lipids [ 20 ]. Recent studies revealed not only that LRG1 is indeed secreted by white and brown adipocytes [ 21 , 22 ] but also that, whereas Lrg1 is similarly transcribed in the liver and adipose tissue, its protein levels are significantly higher in the latter [ 22 ]. On the other hand, endothelial cells appear to express either undetectable or low levels of LRG1 at multiple sites.…”

“…The opposite outcomes of LRG1 inhibition on cell motility described here corroborate the hypothesis that LRG1 exerts the most diverse and conflicting functions through interfering with various signalling pathways, as also exemplified by the different and apparently counterintuitive roles it plays in the heart as described later in this review. Further, it is worth noting that, although the large majority of information related to Lrg1 post transcriptional regulation comes from studies on cancer and other pathological conditions, it is becoming progressively more evident that this may play an important role also in physiology thus explaining some of the discrepancies in mRNA versus protein levels that have been observed, for example, in the liver and adipose tissue [ 22 ].…”

“…Obesity, which is often characterized by chronic low-grade inflammation [ 134 ], plays a critical role in the pathogenesis of various metabolic disorders including insulin resistance, a major risk factor for T2DM. LRG1 levels are significantly higher in the serum and fat depots of obese humans [ 22 ] and positively correlate with BMI, waist circumference and visceral fat mass [ 113 ]. He and colleagues recently uncovered a novel pathogenic role for LRG1 by demonstrating its crucial contribution to high fat diet (HFD) metabolic dysfunctions [ 22 ].…”

“…LRG1 levels are significantly higher in the serum and fat depots of obese humans [ 22 ] and positively correlate with BMI, waist circumference and visceral fat mass [ 113 ]. He and colleagues recently uncovered a novel pathogenic role for LRG1 by demonstrating its crucial contribution to high fat diet (HFD) metabolic dysfunctions [ 22 ]. The authors showed that high levels of circulating LRG1, produced at least partly by distant organ adipocytes, can exacerbate the hepatosteatosis and insulin resistance often observed in HFD by corrupting the normal function of hepatocytes.…”

“…The authors showed that high levels of circulating LRG1, produced at least partly by distant organ adipocytes, can exacerbate the hepatosteatosis and insulin resistance often observed in HFD by corrupting the normal function of hepatocytes. In vitro observations suggest that LRG1 may promote: i) lipid accumulation by suppressing fatty acid catabolism and inducing lipid biosynthesis through activation of the transcription factor SREBP1, and ii) hyperglycemia by downregulating the expression of the insulin receptor substrates IRS1 and IRS2 [ 22 ] (Fig. 5 ).…”