The Acute-Phase Protein Orosomucoid Regulates Food Intake and Energy Homeostasis via Leptin Receptor Signaling Pathway

Abstract

The acute-phase protein orosomucoid (ORM) exhibits a variety of activities in vitro and in vivo, notably modulation of immunity and transportation of drugs. We found in this study that mice lacking ORM1 displayed aberrant energy homeostasis characterized by increased body weight and fat mass. Further investigation found that ORM, predominantly ORM1, is significantly elevated in sera, liver, and adipose tissues from the mice with high-fat diet (HFD)-induced obesity and db/db mice that develop obesity spontaneously due to mutation in the leptin receptor (LepR). Intravenous or intraperitoneal administration of exogenous ORM decreased food intake in C57BL/6, HFD, and leptin-deficient ob/ob mice, which was absent in db/db mice and was significantly reduced in mice with arcuate nucleus (ARC) LepR knockdown, whereas enforced expression of ORM1 in ARC significantly decreased food intake, body weight, and serum insulin level. Furthermore, we found that ORM is able to bind directly to LepR and activate the receptor-mediated JAK2-STAT3 signaling in hypothalamus tissue and GT1-7 cells, which was derived from hypothalamic tumor. These data indicated that ORM could function through LepR to regulate food intake and energy homeostasis in response to nutrition status. Modulating the expression of ORM is a novel strategy for the management of obesity and related metabolic disorders.

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

“…We specifically examined the acute‐phase proteins pentraxin 2/APCS, which in mice serves an analogous role to C‐reactive protein in humans, and Orm1, which has recently been shown to have anorexigenic properties 18, 27, 28. In males, KPC induced a 34.42 ± 6.89‐fold increase in Apcs ( P  < 0.001, n  = 4–5 per group) and a 6.61 ± 0.32‐fold increase in Orm1 relative to controls ( P  < 0.001, n  = 4–5 per group) ( Figure 7A).…”

“…We also found that KPC increases hepatic expression of Orm1 , another key acute‐phase reactant in both mouse and human known to serve numerous important roles in energy balance, immunity, and capillary barrier modulation. Furthermore, ORM1 is of metabolic and behavioural importance because it induces anorexia via leptin receptor signalling in the arcuate nucleus of the hypothalamus 18. In mice, ORM1 is primarily synthesized by the liver and is the only ORM isoform induced in response to inflammatory stimuli.…”

The effects of late gestation nutrient restriction of dams on beef heifer intake, metabolites and hormones during an ad libitum feeding trial

“…() suggest the inability of endothelial cells to transport the hormone across the blood‐brain barrier. Mutated leptin receptors have been observed in obese mice (Sun et al., ). It is unclear what the mechanism behind leptin resistance in this study was.…”

“…Decreased leptin levels in cerebrospinal fluid compared to circulation as shown by Caro et al (1996) suggest the inability of endothelial cells to transport the hormone across the blood-brain barrier. Mutated leptin receptors have been observed in obese mice (Sun et al, 2016).…”

Association of Leptin Receptor Gene Gln223Arg and lys109Arg Polymorphisms with Obesity and Overweight in an Iranian Young Population

“…There can be different causes for disorders in leptin physiological function. Study of mutations and polymorphisms of leptin and leptin receptor genes in the humane and animal models proved the relationship of this protein with obesity (9).…”