Increased glucose consumption distinguishes cancer cells from normal cells and is known as the "Warburg effect" because of increased glycolysis. Lactate dehydrogenase A (LDHA) is a key glycolytic enzyme, a hallmark of aggressive cancers, and believed to be the major enzyme responsible for pyruvate-to-lactate conversion. To elucidate its role in tumor growth, we disrupted both the and genes in two cancer cell lines (human colon adenocarcinoma and murine melanoma cells). Surprisingly, neither nor knockout strongly reduced lactate secretion. In contrast, double knockout (-DKO) fully suppressed LDH activity and lactate secretion. Furthermore, under normoxia, -DKO cells survived the genetic block by shifting their metabolism to oxidative phosphorylation (OXPHOS), entailing a 2-fold reduction in proliferation rates and compared with their WT counterparts. Under hypoxia (1% oxygen), however, suppression completely abolished growth, consistent with the reliance on OXPHOS. Interestingly, activation of the respiratory capacity operated by the-DKO genetic block as well as the resilient growth were not consequences of long-term adaptation. They could be reproduced pharmacologically by treating WT cells with an LDHA/B-specific inhibitor (GNE-140). These findings demonstrate that the Warburg effect is not only based on high LDHA expression, as both and need to be deleted to suppress fermentative glycolysis. Finally, we demonstrate that the Warburg effect is dispensable even in aggressive tumors and that the metabolic shift to OXPHOS caused by / genetic disruptions is responsible for the tumors' escape and growth.

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Major depression is a psychiatric disorder with complex etiology. About 30% of depressive patients are resistant to antidepressants that are currently available, likely because they only target the monoaminergic systems. Thus, identification of novel antidepressants with a larger action spectrum is urgently required. Epidemiological data indicate high comorbidity between metabolic and psychiatric disorders, particularly obesity and depression. We used a well-characterized anxiety/depressive-like mouse model consisting of continuous input of corticosterone for seven consecutive weeks. A panel of reliable behavioral tests were conducted to assessing numerous facets of the depression-like state, including anxiety, resignation, reduced motivation, loss of pleasure, and social withdrawal. Furthermore, metabolic features including weight, adiposity, and plasma biological parameters (lipids, adipokines, and cytokines) were investigated in corticosterone-treated mice. Our data show that chronic administration of corticosterone induced the parallel onset of metabolic and behavioral dysfunctions in mice. AdipoRon, a potent adiponectin receptor agonist, prevented the corticosterone-induced early onset of moderate obesity and metabolic syndromes. Moreover, in all the behavioral tests, daily treatment with AdipoRon successfully reversed the corticosterone-induced depression-like state in mice. AdipoRon exerted its pleiotropic actions on various systems including hippocampal neurogenesis, serotonergic neurotransmission, neuroinflammation, and the tryptophan metabolic pathway, which can explain its antidepressant properties. Our study highlights the pivotal role of the adiponergic system in the development of both metabolic and psychiatric disorders. AdipoRon may constitute a promising novel antidepressant.