Adipose tissue promotes a serum cytokine profile related to lower insulin sensitivity after chronic central leptin infusion

PLoS One. 2012;7(10):e46893. doi: 10.1371/journal.pone.0046893. Epub 2012 Oct 2.


Obesity is an inflammatory state characterized by an augment in circulating inflammatory factors. Leptin may modulate the synthesis of these factors by white adipose tissue decreasing insulin sensitivity. We have examined the effect of chronic central administration of leptin on circulating levels of cytokines and the possible relationship with cytokine expression and protein content as well as with leptin and insulin signaling in subcutaneous and visceral adipose tissues. In addition, we analyzed the possible correlation between circulating levels of cytokines and peripheral insulin resistance. We studied 18 male Wistar rats divided into controls (C), those treated icv for 14 days with a daily dose of 12 μg of leptin (L) and a pair-fed group (PF) that received the same food amount consumed by the leptin group. Serum leptin and insulin were measured by ELISA, mRNA levels of interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4, IL-6, IL-10 and tumor necrosis factor-α (TNF-α) by real time PCR and serum and adipose tissue levels of these cytokines by multiplexed bead immunoassay. Serum leptin, IL-2, IL-4, IFN-γ and HOMA-IR were increased in L and TNF-α was decreased in PF and L. Serum leptin and IL-2 levels correlate positively with HOMA-IR index and negatively with serum glucose levels during an ip insulin tolerance test. In L, an increase in mRNA levels of IL-2 was found in both adipose depots and IFN-γ only in visceral tissue. Activation of leptin signaling was increased and insulin signaling decreased in subcutaneous fat of L. In conclusion, leptin mediates the production of inflammatory cytokines by adipose tissue independent of its effects on food intake, decreasing insulin sensitivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / blood*
  • Cytokines / genetics
  • Eating / drug effects
  • Homeostasis / drug effects
  • Infusion Pumps
  • Insulin / administration & dosage
  • Insulin / blood
  • Insulin / metabolism
  • Insulin / pharmacology
  • Insulin Resistance*
  • Intra-Abdominal Fat / cytology
  • Intra-Abdominal Fat / drug effects*
  • Intra-Abdominal Fat / immunology
  • Intra-Abdominal Fat / metabolism*
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Leptin / administration & dosage
  • Leptin / pharmacology*
  • Male
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Subcutaneous Fat / cytology
  • Subcutaneous Fat / drug effects*
  • Subcutaneous Fat / immunology
  • Subcutaneous Fat / metabolism*
  • Time Factors


  • Cytokines
  • Insulin
  • Leptin
  • RNA, Messenger

Grant support

This work was supported by grants from Fondo de Investigación Sanitaria (PI10/0747), Ministerio de Ciencia y Tecnología (SAF 2010-22277), CIBERobn (CB03/06) and Fundación Endocrinología y Nutrición. S.C. is supported by CIBERobn. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.