Epiregulin induces leptin secretion and energy expenditure in high-fat diet-fed mice

Abstract

Adipokine leptin regulates neuroendocrine circuits that control energy expenditure, thermogenesis, and weight loss. However, canonic regulators of leptin secretion, such as insulin and malonyl CoA, do not support these processes. We hypothesize that epiregulin (EREG), a growth factor that is secreted from fibroblasts under thermogenic and cachexia conditions, induces leptin secretion associated with energy dissipation. The effects of EREG on leptin secretion were studied ex vivo, in the intra-abdominal, white adipose tissue (iAb WAT) explants, as well as in vivo, in wild type mice with diet-induced obesity (DIO) and in ob/ob mice. These mice were pair fed a high-fat diet and treated with intraperitoneal injections of EREG. EREG increased leptin production and secretion in a dose-dependent manner in iAb fat explants via the EGFR/MAPK pathway. After 2 weeks, the plasma leptin concentration was increased by 215% in the EREG treated group compared to the control DIO group. EREG treated DIO mice had an increased metabolic rate and core temperature during the active dark cycle, and displayed cold-induced thermogenesis. EREG treatment reduced iAb fat mass, the major site of leptin secretion, but did not reduce the mass of the other fat depots. In the iAb fat, expression of genes supporting mitochondrial oxidation and thermogenesis was increased in EREG-treated mice vs. control DIO mice. All metabolic and gene regulation effects of EREG-treatment were abolished in leptin-deficient ob/ob mice. Our data revealed a new role of EREG in induction of leptin secretion leading to the energy expenditure state. EREG could be a potential target protein to regulate hypo- and hyperleptinemia, underlying metabolic and immune diseases.

Epiregulin as an Alternative Ligand for Leptin Receptor Alleviates Glucose Intolerance without Change in Obesity

“…A similar decrease in glucose uptake (Figure S2A,B) without changes in plasma insulin levels (Figure S2C) was also observed in our previous study in Lep ob males fed a high-fat diet [24]. A high-fat diet also did not influence weight changes in EREG-treated and control Lep ob males [24]. The glycemic effects of EREG were distinct from the other effects of EREG, including body weight, metabolic rate, and thermogenesis, which are dependent on EGFR receptor and leptin secretion [24].…”

“…The changes in plasma levels of insulin were not significant (Figure 1F), although the insulinotropic activity of EREG was found in vitro [32]. A similar decrease in glucose uptake (Figure S2A,B) without changes in plasma insulin levels (Figure S2C) was also observed in our previous study in Lep ob males fed a high-fat diet [24]. A high-fat diet also did not influence weight changes in EREG-treated and control Lep ob males [24].…”

“…A high-fat diet also did not influence weight changes in EREG-treated and control Lep ob males [24]. The glycemic effects of EREG were distinct from the other effects of EREG, including body weight, metabolic rate, and thermogenesis, which are dependent on EGFR receptor and leptin secretion [24]. Thus, EREG improved glucose uptake under leptin-deficient conditions without affecting other leptin-dependent metabolic pathways such as satiety and energy balance.…”

“…These investigations revealed the predominant expression of Ereg in kidney fibroblasts as well as in neutrophils and resident macrophages in many tissues with the highest levels of Ereg expression in tissues of mesenchymal origin such as bone marrow, lymphoid tissue, and skin. In our previous work, the EREG/EGFR signaling cascade was shown to regulate leptin secretion and activation of LepR to stimulate thermogenesis in white adipose tissue and weight loss [24]. Thermogenic adipocytes have an increased glucose demand that was associated with the increased secretion of EREG, but not the other EGFR ligands [25] (GEO file: 'QS wild type and Aldh1a1 KO preadipocytes 2015 ).…”

Fibroblasts as Modulators of Local and Systemic Cancer Metabolism

“…Though the study focused on cancer cell-derived PTHrP as a key regulator of adipose tissue browning in the LLC system, a link between EGFR ligand production and cancer cachexia is intriguing and warrants further study. Activation of EGFR/MEK signaling in the primary tumor has been recently linked to MEK activation and wasting in host tissues [102], and while CAFs as a source for these ligands or for PTHrP have not been specifically addressed, EGFR signaling has been functionally linked to cachexia and/or energy expenditure in additional systems [103,104]. Providing ligands which act either via tumor cells or directly on adipocytes to promote thermogenesis might suggest a deleterious role for CAFs as promoters of cancer cachexia, and such a role may indeed be tissue- and context-dependent.…”