Astrocytes: new targets of melanocortin 4 receptor actions

  1. Mercedes Lasaga
  1. School of Medicine, Biomedical Research Institute (UBA-CONICET), University of Buenos Aires, Paraguay 2155 piso 10, 1121ABG Buenos Aires, Argentina
    1IFEC (CONICET) Department of Pharmacology, School of Chemistry, National University of Córdoba, Córdoba, Argentina
  1. Correspondence should be addressed to M Lasaga; Email: mlasaga{at}
  1. Figure 1

    Differences between human, mouse, and rat MC4R proteins. Sequence alignment of human, mouse, and rat MC4R protein. Amino acids that differ from the human MC4R sequence are highlighted in gray. Mouse and rat MC4R share 93% of the amino acid sequence with human MC4R and, being very similar, share the same structure. The N-terminal portion is extracellular whereas the C-terminal portion is intracellular. TM, transmembrane domain; IL, intracellular loop; EL, extracellular loop.

  2. Figure 2

    MC4R activation in astrocytes. Activation of MC4R by α-MSH induces production of cAMP, which leads to CREB activation. This pathway is most likely involved in the anti-inflammatory and anti-apoptotic effects of melanocortins in astrocytes. Although NF-κB is involved in the anti-inflammatory effects of melanocortins, this remains a controversial fact for astrocytes. Instead, MC4R activation induces release of the anti-inflammatory agents PPARγ and TGF-β probably through the cAMP-CREB pathway. BDNF released after MC4R activation occurs through cAMP-PKA-CREB in astrocytes and this neurotrophin through TrkB receptor can have direct effects on neurons, promoting their survival. MC4R activation inhibits apoptosis as it increases BCL2 protein levels and reduces Bax protein levels, thus promoting cell survival against apoptotic stimuli in astrocytes as well as in neurons.

  3. Figure 3

    Astrocytes and MC4R in obesity. In response to a HFD diet, the circulation of saturated fatty acids and cytokines is increased. Astrocytes can be activated by both saturated fatty acids and cytokines, and, thus, they respond by increasing GFAP and vimentin expression and by activating NF-κB, which in turn induces cytokine expression. Both cytokines (inflammation) and saturated fatty acids (HFD) promote diet-induced obesity. Stimulation of MC4R by α-MSH reduces astrocyte activation and pro-inflammatory mediators, so it could also be possible that these cells help to induce a decrease in energy balance and thus this may decrease diet-induced obesity susceptibility.

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