Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice

Hepatocyte-derived GDF15 suppresses feeding and improves insulin sensitivity in obese mice

“… 27 Interestingly, differences in body weight in HFD-fed liver-specific Gdf15 KO mice could not be attributed to changes in adipose tissue weight or increased feeding, suggesting the increased liver weight or potentially changes in lean mass, which were not reported, may have contributed. 33 Thus, while a reduction in feeding was consistent with lower body weight gain in our studies, the greater effect on lean mass and observations made in the liver-specific Gdf15 KO mice suggest feeding alone did not account for changes in body composition. One possibility is that the marked hyperinsulinemia ( Figure 2 G) in the KO + GFP mice, alongside more severe hepatic, as opposed to peripheral insulin resistance ( Figures 3 J and 3K), promoted greater increases in lean mass and to a lesser extent fat mass.…”

“…Furthermore, using a variety of approaches, including measuring gene expression from specific cell populations within the stromal vascular or adipocyte fractions of adipose tissue, RNAscope for Gdf15 mRNA in adipose tissue, and myeloid cell-specific Gdf15 KO mice and WT mice with Gdf15 KO bone marrow transplants, the authors demonstrated that changes in adipose tissue Gdf15 expression during obesity are likely due to changes in expression within immune cells and not adipocytes. 33 Despite the modest difference in plasma GDF15 in the KO + FLP mice compared with WT HFD, the subsequent effects of restoring plasma GDF15 on feeding ( Figure 3 A), body weight and composition ( Figures 2 A–2C), and insulin sensitivity ( Figure 3 I), demonstrate that hepatocyte Gdf15 is sufficient for the physiological effects of GDF15.…”

“…During review of our manuscript, a report describing a Gdf15 liver-specific KO line was published that arrived at this same conclusion. 33 Deletion of Gdf15 in liver hepatocytes reduced circulating GDF15 by 50% in HFD-fed mice and resulted in increased body weight, increased liver fat content, and impaired glucose and insulin tolerance. Furthermore, using a variety of approaches, including measuring gene expression from specific cell populations within the stromal vascular or adipocyte fractions of adipose tissue, RNAscope for Gdf15 mRNA in adipose tissue, and myeloid cell-specific Gdf15 KO mice and WT mice with Gdf15 KO bone marrow transplants, the authors demonstrated that changes in adipose tissue Gdf15 expression during obesity are likely due to changes in expression within immune cells and not adipocytes.…”

“…In addition, although our main conclusion is that the hepatocyte is the primary source of circulating GDF15 during obesity, we cannot completely rule out the role of other cell types due to the 30% difference in circulating GDF15 levels that persisted when comparing HFD WT and KO + FLP mice. Although work by Patel and colleagues suggests that adipocytes do not contribute to circulating GDF15 levels during obesity, 33 definitive adipose-specific Gdf15 KO studies have not yet been performed. An additional limitation to our studies was that assessments of glucose homeostasis and insulin sensitivity were only made in KO + GFP and KO + FLP groups.…”

GDF15 Is Required for Cold-Induced Thermogenesis and Contributes to Improve Systemic Metabolic Health Following Loss of OPA1 in Brown Adipocytes

“…Indeed, systemic overexpression of GDF15 was shown to prevent obesity and insulin resistance by modulating metabolic activity and enhancing the expression of important thermogenic and lipolytic genes in BAT and WAT [18][19][20]. GDF15 is secreted by various organs such as liver [21], kidney [22] and skeletal muscle [6]. Recently, studies demonstrated that GDF15 can also be induced in brown adipocytes in response to thermogenic stimuli [23,24] and prolonged high-fat feeding [25].…”