Metabolism alterations are hallmarks of cancer, but the involvement of lipid metabolism in disease progression is unclear. We investigated the role of lipid metabolism in prostate cancer using tissue from patients with prostate cancer and patient-derived xenograft mouse models. We showed that fatty acid uptake was increased in human prostate cancer and that these fatty acids were directed toward biomass production. These changes were mediated, at least partly, by the fatty acid transporter CD36, which was associated with aggressive disease. Deleting Cd36 in the prostate of cancer-susceptible Pten−/− mice reduced fatty acid uptake and the abundance of oncogenic signaling lipids and slowed cancer progression. Moreover, CD36 antibody therapy reduced cancer severity in patient-derived xenografts. We further demonstrated cross-talk between fatty acid uptake and de novo lipogenesis and found that dual targeting of these pathways more potently inhibited proliferation of human cancer-derived organoids compared to the single treatments. These findings identify a critical role for CD36-mediated fatty acid uptake in prostate cancer and suggest that targeting fatty acid uptake might be an effective strategy for treating prostate cancer.

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ized by the onset of muscle weakness and loss of function usually in the late teens and with slow progression (2). Dysferlinopathies include limb-girdle muscular dystrophy type 2B and Miyoshi myopathy, with the proximal and distal limb-girdle muscles being the main muscles affected (2-4). Mouse models of dysferlinopathy harboring dysferlin deficiency or deletion (5-8) consistently have a late onset of dystropathology, by about 8 months of age, with pronounced replacement of myofibers by adipocytes (9). Dysferlin is a member of a large ferlin family of transmembrane proteins that are involved in protein vesicle trafficking and fusion (10), with dysferlin initially attracting attention due to its role in the resealing of experimentally damaged sarcolemma (11-13). Dysferlin is localized in intracellular membranes of skeletal muscles such as Ttubules and sarcoplasmic reticulum (14), plays a role in Ttubule formation (15), and appears to be involved in calcium homeostasis related to excitation-contraction coupling (16-18). Dysferlin is highly expressed in skeletal myofibers but is also present in many other tissues (19) and cells, including adipocytes (20), macrophages (21), and endothelium (22). Two striking features of human and mouse dysferlin-deficient muscles are the accumulation of many lipid droplets within myofibers and, at a later age, the apparent replacement of myofibers with extramyocellular adipocytes (9, 15). Histopathology is not evident in young mice aged 3 months but is pronounced by 8-12 months in some muscles, including psoas and quadriceps, with increasing severity by 19 months (23). Indeed, in older Dysf-deficient A/J mice, 20% to 40% of the myofibers in quadriceps and psoas muscles are replaced by adipocytes (15, 23). In humans, Abstract Defects in the gene coding for dysferlin, a membrane-associated protein, affect many tissues, including skeletal muscles, with a resultant myopathy called dysferlinopathy. Dysferlinopathy manifests postgrowth with a progressive loss of skeletal muscle function, early intramyocellular lipid accumulation, and a striking later replacement of selective muscles by adipocytes. To better understand the changes underpinning this disease, we assessed whole-body energy homeostasis, skeletal muscle fatty acid metabolism, lipolysis in adipose tissue, and the skeletal muscle lipidome using young adult dysferlin-deficient male BLAJ mice and age-matched C57Bl/6J WT mice. BLAJ mice had increased lean mass and reduced fat mass associated with increased physical activity and increased adipose tissue lipolysis. Skeletal muscle fatty acid metabolism was remodeled in BLAJ mice, characterized by a partitioning of fatty acids toward storage rather than oxidation. Lipidomic analysis identified marked changes in almost all lipid classes examined in the skeletal muscle of BLAJ mice, including sphingolipids, phospholipids, cholesterol, and most glycerolipids but, surprisingly, not triacylglycerol. These observations indicate that an early manifestation of dysferlin deficiency is the repro...

Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass associated with significant functional impairment. Cachexia robs patients of their strength and capacity to perform daily tasks and live independently. Effective treatments are needed urgently. Here, we investigated the therapeutic potential of activating the "alternative" axis of the renin-angiotensin system, involving ACE2, angiotensin-(1-7), and the mitochondrial assembly receptor (MasR), for treating cancer cachexia. Plasmid overexpression of the MasR or pharmacologic angiotensin-(1-7)/ MasR activation did not affect healthy muscle fiber size in vitro or in vivo but attenuated atrophy induced by coculture with cancer cells in vitro. In mice with cancer cachexia, the MasR agonist AVE 0991 slowed tumor development, reduced weight loss, improved locomotor activity, and attenuated muscle wasting, with the majority of these effects dependent on the orexigenic and not antitumor properties of AVE 0991. Proteomic profiling and IHC revealed that mechanisms underlying AVE 0991 effects on skeletal muscle involved miR-23a-regulated preservation of the fast, glycolytic fibers. MasR activation is a novel regulator of muscle phenotype, and AVE 0991 has orexigenic, anticachectic, and antitumorigenic effects, identifying it as a promising adjunct therapy for cancer and other serious muscle wasting conditions. Significance: These findings demonstrate that MasR activation has multiple benefits of being orexigenic, anticachectic, and antitumorigenic, revealing it as a potential adjunct therapy for cancer.

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Study background: Insulin resistance plays an important role in the pathogenesis of type2 diabetes and the metabolic syndrome. Many of the genes and pathways involved have been identified but some remain to be defined. Metallothioneins (Mts) are a family of anti-oxidant proteins and metallothionein 2a (Mt2a) polymorphims have been recently associated with type 2 diabetes and related complications. Our objective was to determine Mt2a gene expression levels in adipose tissues from diabetic patients and determine the effect of Mt treatment on adipocyte insulin sensitivity. Methods: Samples of subcutaneous and visceral adipose tissues from lean, type 2 diabetic and non-diabetic obese patients were analysed using RT-qPCR for Mt2a mRNA abundance. The regulation of Mt2a expression was further studied in 3T3-L1 adipocytes treated or not with TNFα (10 ng/ml, 72 h) to induce insulin resistance. The effects of Mt on glucose uptake were investigated in cultured adipocytes treated with recombinant Mt protein. Results: We found that Mt2a gene expression was significantly higher in adipose tissue of type 2 diabetic patients in comparison to lean (p=0.003) subjects. In 3T3-L1 adipocytes, insulin resistance induced by TNFα increased Mt2a mRNA levels (p=3×10-4) and insulin-stimulated glucose uptake was significantly inhibited by 53% (p=8×10-4) compared to vehicle, when 3T3-L1 adipocytes were treated with Mt protein. Conclusions: These data suggest that Mt2a might be involved in insulin resistance through the up-regulation of Mt gene expression, which may lead to the modulation of insulin action in fat cells. These results suggest the concept of considering Mt proteins as markers and potential targets in type 2 diabetes.

<p>This file contains: • Supplemental Methods • Supplemental Figure S1. Muscle-specific overexpression of the AT1 but not the MasR regulates skeletal muscle fiber size in healthy mice. • Supplemental Figure S2. Representative images of differentiated C2C12 myotubes incubated for 48 h in normal horse serum and treated with vehicle control or the ACE/Ang II/AT1 axis activators Ang II or A779 • Supplemental Figure S3. Genetic MasR overexpression was induced by transducing C2C12 myoblasts with a Tet-regulated MasR lentivirus or empty lentivirus and treating differentiated myotubes with doxycylin • Supplemental Figure S4. Low dose AVE 0991 induces small but significant improvements in food and water intake and weight loss in severely cachectic C-26 tumor-bearing mice • Supplemental Figure S5. Low dose AVE 0991 (1 mg/kg) causes an oxidative-to-glycolytic shift in fiber types in TA muscles from severely cachectic C-26 tumor-bearing mice • Supplemental Figure S6. High dose AVE 0991 treatment enhanced cumulative water intake and movement as assessed by the number of beam breaks in severely cachectic C-26 tumor-bearing mice fed ad libitum but not in those pair-fed to vehicle treated controls • Supplemental Figure S7. Pharmacological Ang-(1-7)/MasR activation protects against Lewis Lung Carcinoma (LLC) cancer cell induced muscle fiber atrophy in vitro • Supplemental Figure S8. Specificity of our custom anti-AT1 peptide compared to a commercially available anti-AT1 antibody • Supplemental Table S1. Primers used to amplify AT1 and MasR genes • Supplemental Table S2. Human cancer cachexia study group characteristics • Supplemental Table S3. List of upregulated proteins in AVE 0991 treated serum starved myotubes • Supplemental Table S4. List of down regulated proteins in AVE 0991 treated serum starved myotubes</p>