The metabolic actions of the ghrelin gene-derived peptide obestatin are still unclear. We investigated obestatin effects in vitro, on adipocyte function, and in vivo, on insulin resistance and inflammation in mice fed a high-fat diet (HFD). Obestatin effects on apoptosis, differentiation, lipolysis, and glucose uptake were determined in vitro in mouse 3T3-L1 and in human subcutaneous (hSC) and omental (hOM) adipocytes. In vivo, the influence of obestatin on glucose metabolism was assessed in mice fed an HFD for 8 wk. 3T3-L1, hSC, and hOM preadipocytes and adipocytes secreted obestatin and showed specific binding for the hormone. Obestatin prevented apoptosis in 3T3-L1 preadipocytes by increasing phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK)1/2 signaling. In both mice and human adipocytes, obestatin inhibited isoproterenol-induced lipolysis, promoted AMP-activated protein kinase phosphorylation, induced adiponectin, and reduced leptin secretion. Obestatin also enhanced glucose uptake in either the absence or presence of insulin, promoted GLUT4 translocation, and increased Akt phosphorylation and sirtuin 1 (SIRT1) protein expression. Inhibition of SIRT1 by small interfering RNA reduced obestatin-induced glucose uptake. In HFD-fed mice, obestatin reduced insulin resistance, increased insulin secretion from pancreatic islets, and reduced adipocyte apoptosis and inflammation in metabolic tissues. These results provide evidence of a novel role for obestatin in adipocyte function and glucose metabolism and suggest potential therapeutic perspectives in insulin resistance and metabolic dysfunctions.

Perinatal HIV-1 infection interferes with sexual maturation. The mechanisms by which this occurs should be elucidated and intervention strategies designed. Intervention could save much psychological distress, since associated linear growth failure can exacerbate adolescents' feelings of being different and unwell.

Changes in the homeostasis of tumor necrosis factor a (TNFa) have been demonstrated in patients and experimental models of amyotrophic lateral sclerosis (ALS). However, the contribution of TNFa to the development of ALS is still debated. TNFa is expressed by glia and neurons and acts through the membrane receptors TNFR1 and TNFR2, which may have opposite effects in neurodegeneration. We investigated the role of TNFa and its receptors in the selective motor neuron death in ALS in vitro and in vivo. TNFR2 expressed by astrocytes and neurons, but not TNFR1, was implicated in motor neuron loss in primary SOD1-G93A co-cultures. Deleting TNFR2 from SOD1-G93A mice, there was partial but significant protection of spinal motor neurons, sciatic nerves, and tibialis muscles. However, no improvement of motor impairment or survival was observed. Since the sciatic nerves of SOD1-G93A/TNFR2À/À mice showed high phospho-TAR DNA-binding protein 43 (TDP-43) accumulation and low levels of acetyl-tubulin, two indices of axonal dysfunction, the lack of symptom improvement in these mice might be due to impaired function of rescued motor neurons. These results indicate the interaction between TNFR2 and membrane-bound TNFa as Abbreviations used: ALS, amyotrophic lateral sclerosis; Ara-C, arabinoside; BDNF, brain-derived neurotrophic factor; ChAT, choline acetyl transferase; CSF, cerebrospinal fluid; DIV, days in vitro; GFAP, glial fibrillary acidic protein; HBSS, Hank's balanced salt solution; IFNc, interferon c; IL-1b, interleukin 1b; IL-6, interleukin 6; iNOS, inducible NO synthase; LPS, lipopolysaccharides; mTNFa, membrane TNFa; NGS, normal goat serum; NMJ, neuromuscular junctions; PBS, phosphate-buffered saline; PFA, paraformaldehyde; qPCR, quantitative polymerase chain reaction; SDS, sodium dodecyl sulphate; SOD1, superoxide dismutase 1; sTNFa, soluble TNFa; sTNFR2, soluble TNFR2; TBS, tris-buffered solution; TBS-T, tris-buffered solution with Tween; TDP-43, TAR DNA-binding protein 43; Teff, T effector cells; TNFa, tumor necrosis factor a; TNFR1, tumor necrosis factor receptor 1; TNFR2, tumor necrosis factor receptor 2; Treg, regulatory T cells. an innovative pathway involved in motor neuron death. Nevertheless, its inhibition is not sufficient to stop disease progression in ALS mice, underlining the complexity of this pathology.

These data may be of use in the design of effective non-surgical PCa ablations that combine tumor destruction with long lasting immunity.

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