Elucidating the role of leptin in systemic inflammation: a study targeting physiological leptin levels in rats and their macrophages

Abstract

To elucidate the role of leptin in acute systemic inflammation, we investigated how its infusion at low, physiologically relevant doses affects the responses to bacterial lipopolysaccharide (LPS) in rats subjected to 24 h of food deprivation. Leptin was infused subcutaneously (0-20 μg·kg·h) or intracerebroventricularly (0-1 μg·kg·h). Using hypothermia and hypotension as biomarkers of systemic inflammation, we identified the phase extending from 90 to 240 min post-LPS as the most susceptible to modulation by leptin. In this phase, leptin suppressed the rise in plasma TNF-α and accelerated the recoveries from hypothermia and hypotension. Suppression of TNF-α was not accompanied by changes in other cytokines or prostaglandins. Leptin suppressed TNF-α when infused peripherally but not when infused into the brain. Importantly, the leptin dose that suppressed TNF-α corresponded to the lowest dose that limited food consumption; this dose elevated plasma leptin within the physiological range (to 5.9 ng/ml). We then conducted in vitro experiments to investigate whether an action of leptin on macrophages could parallel our in vivo observations. The results revealed that, when sensitized by food deprivation, LPS-stimulated peritoneal macrophages can be inhibited by leptin at concentrations that are lower than those reported to promote cytokine release. It is concluded that physiological levels of leptin do not exert a proinflammatory effect but rather an anti-inflammatory effect involving selective suppression of TNF-α via an action outside the brain. The mechanism of this effect might involve a previously unrecognized, suppressive action of leptin on macrophage subpopulations sensitized by food deprivation, but future studies are warranted.

Site-Specific Reprogramming of Macrophage Responsiveness to Bacterial Lipopolysaccharide in Obesity

“…By culturing freshly excised resident macrophages under identical conditions, our intention was to eliminate their modulation by extrinsic factors that make up the distinct tissue microenvironment of obese vs. lean animals. Such factors include hormones with immunomodulatory actions (17, 30, 31), in addition to cytokines, lipid-derived mediators and gaseous transmitters (32). In the absence of such factors, diet-dependent changes in macrophage biology likely reflect reprogramming of their intrinsic properties.…”

“…One way to dissect out these factors is to extract macrophages from the distinct tissue microenvironments of obese vs. lean animals, so that they can be subsequently studied ex vivo under identical conditions. Using this sort of approach, we have observed that even a brief change in energy balance (24 h of food deprivation) is able to reprogram the intrinsic responsiveness to LPS in certain macrophage subpopulations (17). Thus, prominent changes in the intrinsic program of macrophages to LPS can be expected in obese animals chronically maintained on a high-fat diet (HFD).…”

Protective effects of leptin against cerebral ischemia/reperfusion injury (Review)

“…In addition, neutrophil adhesion to vascular endothelial cells inhibited the production of NO, as determined by the aggravation of cell edema (74). Leptin has an anti-inflammatory role (75,76); it activates the nuclear factor-κB pathway, inhibits the expression of pro-inflammatory factors [tumor necrosis factor (TNF)-α, IL-6, IL-1β] within 7 h and increases the expression of IL-10 (74,77) Within 100 min, the human body is able to recover from hypothermia and hypotension caused by ischemia/reperfusion injury (78). Within 90–240 min, TNF-α is inhibited.…”

Microbiome and morbid obesity increase pathogenic stimulus diversity

“…Physiological levels of leptin result in selective suppression of TNFa in macrophage subpopulations by food withdrawal as a centrally mediated anti-inflammatory effect, which is incompletely understood [149].…”