Tissue-specific metabolic profile drives iNKT cell function during obesity and liver injury.

Invariant natural killer T (iNKT) cells are a distinct population of lymphocytes characterized by their reactivity to glycolipids presented by CD1d. iNKT cells are found throughout the body, and little is known about their tissue-specific metabolic regulation. Here, we show that splenic and hepatic iNKT cells are metabolically comparable and rely on glycolytic metabolism to support their activation. Deletion of the pyruvate kinase M2 (Pkm2) gene in splenic and hepatic iNKT cells impairs their response to specific stimulation and their ability to mitigate acute liver injury. In contrast, adipose tissue (AT) iNKT cells exhibit a distinctive immunometabolic profile, with AMP-activated protein kinase (AMPK) being necessary for their function. AMPK deficiency impairs AT-iNKT physiology, blocking their capacity to maintain AT homeostasis and their ability to regulate AT inflammation during obesity. Our work deepens our understanding on the tissue-specific immunometabolic regulation of iNKT cells, which directly impacts the course of liver injury and obesity-induced inflammation.

aPKC-Mediated Persistent Increase in AMPA/NMDA Ratio in the VTA Participates in the Neuroadaptive Signal Necessary to Induce NAc Synaptic Plasticity After Cocaine Administration.

Chronic cocaine exposure produces enduring neuroadaptations in the brain's reward system. Persistence of early cocaine-evoked neuroadaptations in the ventral tegmental area (VTA) is necessary for later synaptic alterations in the nucleus accumbens (NAc), suggesting a temporal sequence of neuroplastic changes between these two areas. However, the molecular nature of the signal that mediates this sequential event is unknown. Here we used the behavioral sensitization model and the aPKC inhibitor of late-phase LTP maintenance, ZIP, to investigate if a persistent increase in AMPA/NMDA ratio plays a role in the molecular mechanism that allows VTA neuroadaptations to induce changes in the NAc. Results showed that intra-VTA ZIP microinfusion successfully blocked cocaine-evoked synaptic enhancement in the VTA and the expected AMPA/NMDA ratio decrease in the NAc following cocaine sensitization. ZIP microinfusions also blocked the expected AMPA/NMDA ratio increase in the NAc following cocaine withdrawal. These results suggest that a persistent increase in AMPA/NMDA ratio, mediated by aPKCs, could be the molecular signal that enables the VTA to elicit synaptic alterations in the NAc following cocaine administration.

Pyruvate Kinase M2: A Potential Target for Regulating Inflammation.

Pyruvate kinase (PK) is the enzyme responsible for catalyzing the last step of glycolysis. Of the four PK isoforms expressed in mammalian cells, PKM2 has generated the most interest due to its impact on changes in cellular metabolism observed in cancer as well as in activated immune cells. As our understanding of dysregulated metabolism in cancer develops, and in light of the growing field of immunometabolism, intense efforts are in place to define the mechanism by which PKM2 regulates the metabolic profile of cancer as well as of immune cells. The enzymatic activity of PKM2 is heavily regulated by endogenous allosteric effectors as well as by intracellular signaling pathways, affecting both the enzymatic activity of PKM2 as a PK and the regulation of the recently described non-canonical nuclear functions of PKM2. We here review the current literature on PKM2 and its regulation, and discuss the potential for this protein as a therapeutic target in inflammatory disorders.