Peripheral but not central leptin prevents the immunosuppression associated with hypoleptinemia in rats

Abstract

Leptin is a peripheral immunoenhancing reagent that directly activates splenic lymphocytes in mice. We found that a 48 h fast in rats resulted in a decrease in serum leptin that was accompanied by a lower delayed-type hypersensitivity (DTH) response. Peripheral leptin replacement completely restored this response in fasted animals. We employed a recombinant adeno-associated virus (rAAV) system to deliver leptin gene directly into rat brain to assess the effect of sustained long-term central expression of leptin on immune responses. The rAAV-leptin rats had elevated central leptin over the 60 day duration of the experiment, whereas body fat and circulating leptin fell to near zero levels. The DTH response was significantly reduced by 10-20% in rats receiving rAAV-leptin compared with the control rats, and the difference was maintained for over 50 h. When the rats undergoing rAAV-leptin gene therapy were given either murine recombinant leptin or PBS s.c., rats receiving leptin had a 17% higher DTH response than rats receiving PBS. The isolated splenocytes from the former group also proliferated 34% more in vitro in response to the mitogen concanavalin A as compared with the latter group. These results suggest that peripheral leptin has a dominant role in maintaining T-cell-mediated immune responses in rats, and central leptin is unable to compensate for the immunosuppression associated with peripheral hypoleptinemia. Furthermore, preservation of normal cell-mediated immune responses does not require fat tissue as along as serum leptin levels are maintained.

Leptin as an immunomodulator

“…Similarly, humans with congenital leptin deficiency have a much higher incidence of infection-related death during childhood (Ozata et al, 1999), whereas recombinant human leptin (rmetHuLeptin) administration in two children with congenital leptin deficiency normalized absolute numbers of naive CD4 + CD45RA + T cells and nearly restored the proliferation response and the cytokine release profile from their lymphocytes (Farooqi et al, 2002). A number of studies in mice have shown that the effect of leptin on the immune system is both direct and indirect, i.e., via modulation of central or peripheral pathways (Fraser et al, 1999;Zhang et al, 2002).…”

Leptin in Immunology

“…A number of studies in mice have shown that the effect of leptin on the immune system is both direct and indirect, i.e., via modulation of central or peripheral pathways (28,29).…”

Hypothalamic delivery of doxycycline-inducible leptin gene allows for reversible transgene expression and physiological responses

“…For example, a single intracerebroventricular (i.c.v) injection of constitutively active rAAV-leptin was recently shown to impair T-lymphocyte-mediated immunity in rats. 22 As discussed previously, leptin overexpression could also have negative effects on the reproductive system 10 and skeletal system. 11 Should such sideeffects appear, transgene expression could be reduced or silenced if the gene delivery system incorporates regulation.…”