Abstract
In the mouse, the osteoblast-derived hormone Lipocalin-2 (LCN2) suppresses food intake and acts as a satiety signal. We show here that meal challenges increase serum LCN2 levels in persons with normal or overweight, but not in individuals with obesity. Postprandial LCN2 serum levels correlate inversely with hunger sensation in challenged subjects. We further show through brain PET scans of monkeys injected with radiolabeled recombinant human LCN2 (rh-LCN2) and autoradiography in baboon, macaque, and human brain sections, that LCN2 crosses the blood-brain barrier and localizes to the hypothalamus in primates. In addition, daily treatment of lean monkeys with rh-LCN2 decreases food intake by 21%, without overt side effects. These studies demonstrate the biology of LCN2 as a satiety factor and indicator and anorexigenic signal in primates. Failure to stimulate postprandial LCN2 in individuals with obesity may contribute to metabolic dysregulation, suggesting that LCN2 may be a novel target for obesity treatment.
Highlights
Obesity is a global epidemic that results in millions of deaths every year; a chronic disease associated with other serious and chronic conditions including type 2 diabetes, coronary artery disease, stroke, cancer, and depression amongst others (Heymsfield and Wadden, 2017)
To assess the postprandial regulation of serum LCN2, we used data from four separate studies where healthy individuals with normal weight, overweight, obesity, and severe obesity were challenged with a meal after an overnight fast
We examined the translational and therapeutic potential of LCN2, and we found that LCN2 crosses the blood-brain barrier (BBB), localizes to the hypothalamus, and suppresses food intake in non-human primates
Summary
Obesity is a global epidemic that results in millions of deaths every year; a chronic disease associated with other serious and chronic conditions including type 2 diabetes, coronary artery disease, stroke, cancer, and depression amongst others (Heymsfield and Wadden, 2017). Previous studies in mice show that a hormone called Lipocalin-2 (LCN2) suppresses appetite It reduces body weight and improves sugar metabolism in the animals. Whether this hormone has the same effects in humans or other primates is unclear. The hormone suppressed food intake and lowered body weight without toxic effects in short-term studies. There are limited effective medical treatment options for long-term weight loss mainly due to our limited understanding of energy homeostasis—the mechanism that sustains weight by matching energy intake to energy expenditure over time (Schwartz et al, 2017). Long-term LCN2 administration to lean and obese mice suppresses appetite and body weight gain without loss of effect over time, and improves whole body glucose metabolism while at the same time increasing energy expenditure. Molecular, and biochemical studies in mice (Mosialou et al, 2017; Rached et al, 2010) we sought to determine whether the postprandial regulation and hypothalamic action of LCN2 is conserved in humans and non-human primates and whether the systemic administration of LCN2 in primates induces appetite suppression
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