Leptin and the Proinflammatory State Associated with Human Obesity

Abstract

It has been suggested that elevated leptin levels underlie the low grade proinflammatory state in human obesity. We reasoned that if elevated leptin levels are an important factor in the proinflammatory state in obesity, then exogenous leptin administration during weight loss should counteract the concurrent beneficial effects of weight loss on the proinflammatory state. We therefore determined whether long-acting pegylated recombinant leptin (PEG-OB) prevents the decrease in cellular and humoral inflammation parameters during a very low calorie diet in healthy overweight young men. Except for B cells, PEG-OB treatment did not influence the decline in total leukocyte count and mononuclear subfractions during the diet. Weight loss decreased the humoral inflammation parameters TNFalpha, tissue plasminogen activator, and von Willebrand factor (P < 0.05), but in combination with PEG-OB treatment, a significant decrease was shown for inflammation markers as a whole (P < 0.014) and that of the individual parameters tissue plasminogen activator, von Willebrand factor, plasminogen activator inhibitor type 1, and intercellular adhesion molecule-1 (P < 0.05). The increase in C-reactive protein levels (P < 0.05) was the sole indication for a humoral proinflammatory action of leptin. Although PEG-OB treatment significantly increased weight loss (P < 0.03), the data do not support a proinflammatory role of leptin in human obesity.

Ovariectomy and estrogen treatment modulate iron metabolism in rat adipose tissue

“…Leptin might play a role in regulating iron metabolism in overweight status because it shares a number of common biological features with interleukin (IL)-6, a cytokine released in response to inflammation, a condition often associated with obesity [41]. induces an increase of hepcidin secretion from liver cells [42], that in turn negatively regulates systemic iron metabolism by directly interacting with ferroportin (FPN1), a protein devoted to control the cellular iron efflux [43].…”

Increased leptin expression selectively in the hypothalamus suppresses inflammatory markers CRP and IL-6 in leptin-deficient diabetic obese mice

“…A similar outcome of a single central injection of rAAV-lep persisting for longer periods was observed in wt rodents and ob/ ob mice [6][7][8][9]14,32,46,47]. The efficacy of the stable leptin expression, specifically in the hypothalamus in minute amounts, to curb accumulation of fat for the lifetime of rodents is important because excessive long-term secretion of several adipokines contributes to a state of chronic, systemic and local vascular inflammation as the volume of adipose tissue, especially visceral adipose tissue, expands [19,21,33,34,36,38,42,45]. The co-morbidities of obesity, in particular CVD and diabetes, are hypothesized to be due, in part, to persistence of chronic lowgrade, subclinical inflammation.…”

“…The fourth new finding of this investigation relates to the role of hyperleptinemia in causing chronic low-grade inflammation and secretions of pro-inflammatory CVD markers [21,28,34,42]. Although a positive relationship between hyperleptinemia and high levels of IL-6 and CRP have been observed in obese patients, experimental evidence that peripheral actions of leptin on targets in the periphery engenders these relationships is scarce.…”

“…Positive correlations between plasma leptin and CRP concentrations with increasing adiposity have been reported. Administration of leptin to humans was also shown to increase blood CRP levels [21,34]. The evidence that leptin can stimulate the production of CRP by cultured human hepatocytes implied that leptin may play a role in the physiological regulation of CRP [11].…”

Human visceral adipose tissue and the plasminogen activator inhibitor type 1

“…Low-density lipoprotein (LDL) cholesterol was calculated with the Friedewald formula. 13 GH concentrations were measured with a sensitive time-resolved fluoroimmunoassay (Wallac, Turku, Finland), specific for the 22-kDa GH protein, and plasma FFA levels were determined by the NEFA-C FFA kit (Wako Chemicals, Neuss, Germany). Plasma IL-1a, IL-6, TNFa, transforming growth factor-b (TGFb), soluble intercellular adhesion molecule-1 (sICAM-1) and tissue plasminogen activator (tPA) were assessed by commercially available ELISA kits: PeliKane compact kit (CLB, Amsterdam, the Netherlands) for IL-6, HS Quantikine (R&D Systems, Abingdon, UK) for IL-1a, TNFa, TGFb and ICAM-1 and Imulyse (Biopool, Umeå, Sweden) for tPA.…”