AMP-activated protein kinase (AMPK) functions as a fuel sensor in the cell and is activated when cellular energy is depleted. Here we report that alpha-lipoic acid (alpha-LA), a cofactor of mitochondrial enzymes, decreases hypothalamic AMPK activity and causes profound weight loss in rodents by reducing food intake and enhancing energy expenditure. Activation of hypothalamic AMPK reverses the effects of alpha-LA on food intake and energy expenditure. Intracerebroventricular (i.c.v.) administration of glucose decreases hypothalamic AMPK activity, whereas inhibition of intracellular glucose utilization through the administration of 2-deoxyglucose increases hypothalamic AMPK activity and food intake. The 2-deoxyglucose-induced hyperphagia is reversed by inhibiting hypothalamic AMPK. Our findings indicate that hypothalamic AMPK is important in the central regulation of food intake and energy expenditure and that alpha-LA exerts anti-obesity effects by suppressing hypothalamic AMPK activity.

Mucormycosis is a life-threatening infection caused by Mucorales fungi. Here we sequence 30 fungal genomes, and perform transcriptomics with three representative Rhizopus and Mucor strains and with human airway epithelial cells during fungal invasion, to reveal key host and fungal determinants contributing to pathogenesis. Analysis of the host transcriptional response to Mucorales reveals platelet-derived growth factor receptor B (PDGFRB) signaling as part of a core response to divergent pathogenic fungi; inhibition of PDGFRB reduces Mucorales-induced damage to host cells. The unique presence of CotH invasins in all invasive Mucorales, and the correlation between CotH gene copy number and clinical prevalence, are consistent with an important role for these proteins in mucormycosis pathogenesis. Our work provides insight into the evolution of this medically and economically important group of fungi, and identifies several molecular pathways that might be exploited as potential therapeutic targets.

e Mucormycosis is a life-threatening fungal infection almost uniformly affecting diabetics in ketoacidosis or other forms of acidosis and/or immunocompromised patients. Inhalation of Mucorales spores provides the most common natural route of entry into the host. In this study, we developed an intratracheal instillation model of pulmonary mucormycosis that hematogenously disseminates into other organs using diabetic ketoacidotic (DKA) or cyclophosphamide-cortisone acetate-treated mice. Various degrees of lethality were achieved for the DKA or cyclophosphamide-cortisone acetate-treated mice when infected with different clinical isolates of Mucorales. In both DKA and cyclophosphamide-cortisone acetate models, liposomal amphotericin B (LAmB) or posaconazole (POS) treatments were effective in improving survival, reducing lungs and brain fungal burdens, and histologically resolving the infection compared with placebo. These models can be used to study mechanisms of infection, develop immunotherapeutic strategies, and evaluate drug efficacies against life-threatening Mucorales infections. Mucormycoses are uncommon life-threatening fungal infections caused by fungi of the order Mucorales (1-3). These infections almost uniformly afflict the immunocompromised hosts, those with diabetic ketoacidosis (DKA) or other forms of acidosis, and trauma patients (e.g., victims of the recent natural disasters of the Joplin tornado [4] and the Indian tsunami [5]) (6, 7). Due to the rising prevalence of diabetes, cancer, and organ transplantation in aging populations, as well as the recent increase in natural disasters, the number of patients at risk for this deadly infection is significantly rising and is expected to continue to rise (8-10).Fungi belonging to the order Mucorales are distributed into six families, all of which can cause cutaneous and hematogenously disseminated infections (1, 6). Species belonging to the family Mucoraceae are isolated more frequently from patients with mucormycosis than any other family. Among the Mucoraceae, Rhizopus spp. are the most common cause of mucormycosis and are responsible for approximately 70% of all infections and 90% of rhinocerebral cases (6,11,12). However, recently more cases caused by the previously less frequent species of Lichtheimia (formerly Absidia) corymbifera, Apophysomyces elegans, and Mucor species have been reported (4, 6, 13-17). Increasing numbers of cases of mucormycosis have been also reported due to infection with Cunninghamella spp. (18)(19)(20).Despite disfiguring surgical debridement and adjunctive antifungal therapy, the overall mortality of mucormycosis remains approximately 50%. In the absence of surgical removal of the infected focus, antifungal therapy alone is rarely curative, resulting in a 100% mortality rate for patients with hematogenously disseminated disease (1,9,(21)(22)(23)(24). Clearly, new strategies to prevent and treat mucormycosis are urgently needed. Because of the rarity of the disease, controlled clinical trials are hard to conduct. Consequently...