Innate and adaptive immune responses perform critical functions in host defense, tissue injury and tissue remodeling. Although these inflammatory responses can be life-saving during times of infection or tissue damage, uncontrolled inflammation contributes to the pathogenesis of various degenerative, autoimmune, and metabolic diseases, including multiple sclerosis, arthritis, atherosclerosis, and type 2 diabetes. For instance, inflammatory activation of macrophages and the release of T helper 1 (TH1) type inflammatory cytokines like tumor necrosis factor α, interleukin-6, and interleukin-1β are closely linked to the pathogenesis of obesity and the detrimental sequelae of insulin resistance and metabolic syndrome. In the past, the development of new therapeutic interventions to treat this inflammatory response focused on either blockade of these inflammatory cytokines, or suppression of the downstream signaling pathways that these cytokines activate. However, biasing the immune response toward the TH2 axis was an alternative approach that successfully attenuated TH1-type inflammation in murine models of autoimmunity without the attendant immunosuppressive sequelae. I hypothesized that the anti-inflammatory axis driven by TH2 type responses could ameliorate the detrimental effects of obesity-induced insulin resistance and metabolic syndrome. I approached this hypothesis from two independent but complementary angles: (1) identification of transcriptional regulators that promote alternative macrophage activation, and (2) disruption (loss of function) and activation (gain of function) of the TH2 axis of inflammation.
During a search for genetic pathways that control alternative macrophage activation, our lab identified the peroxisome proliferator-activated receptor (PPAR)-γ, a sensor of fatty acids, as a gene that was markedly induced in macrophages stimulated with interleukin-4 (IL-4). We generated mice with a macrophage-specific deletion of PPARγ, and showed that PPARγ was critical for the maturation of alternatively activated macrophages. Disruption of PPARγ in myeloid cells impaired alternative macrophage activation, and thereby predisposed these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. In addition, we showed that in response to IL-4, PPARδ directed the expression of the alternative phenotype in liver macrophages (Kupffer cells) of lean and obese mice. Importantly, adoptive transfer of PPARδ−/− bone marrow into wild type mice diminished alternative activation of hepatic macrophages, which caused hepatic dysfunction and insulin resistance. Suppression of hepatic oxidative metabolism was recapitulated by co-culturing hepatocytes with PPARδ−/− macrophages or their conditioned media, which indicated the direct involvement of Kupffer cells in controlling liver lipid metabolism. Altogether, these experiments demonstrate that alternative activation of adipose tissue macrophages and Kupffer cells plays a central role in the maintenance of glucose and lipid homeostasis.
Since it is well established that TH1-type inflammation contributes to the pathogenesis of obesity-induced insulin resistance, I reasoned that biasing the adaptive immune response towards the TH2-axis would mitigate the metabolic sequelae of obesity. Genetic disruption of signal transducer and activator of transcription 6 (STAT6), the mediator of TH2-type immune responses, inhibited insulin action, while administration of the T H2 cytokine interleukin-4 (IL-4) improved glucose tolerance and insulin sensitivity in obese mice. The anti-diabetic effects of the IL-4/STAT6 axis were partially, mediated by regulation of hepatic fuel selection via inhibition of peroxisome proliferator-activated receptor α (PPARα).
Since mice unable to activate the TH2 axis of inflammation exhibited marked impairment in nutrient homeostasis, I explored the role of the signal transducer and activator of transcription 4 (STAT4), a key transcriptional regulator of TH1 responses, in glucose and lipid homeostasis. STAT4 null mice were resistant to diet-induced glucose intolerance. Strikingly, STAT4 deficient mice exhibited fasting hypoglycemia, due in part to blunted expression of the transcriptional program associated with the fasting response. Moreover, fasting induced interleukin-12 (IL-12) production by liver Kupffer cells. IL-12 was able to synergize with gluconegenic factors to increase the expression of genes associated with the fasting response.
Together, these findings identify a new biological function for T H2 and TH1 immunity in the regulation of energy homeostasis. I show that activation of the TH2 inflammatory program ameliorates the harmful effects of obesity, and I identify STAT6 as a key transcriptional regulator of energy homeostasis. Moreover, I show that the TH1 signaling pathway is critical to the initiation of the fasting response. Thus, my thesis work uncovers novel transcriptional crosstalk between the immune and metabolic systems, indicating that these programs might have coevolved to control essential functions in metazoans.
|School Location:||United States -- California|
|Source:||DAI-B 70/10, Dissertation Abstracts International|
|Subjects:||Medicine, Physiology, Immunology|
|Keywords:||Gluconeogenesis, Immune responses, Insulin resistance, Lipid homeostasis, Macrophages, Tissue engineering|
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