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The role of integrins, in particular αv integrins, in regulating insulin resistance is incompletely understood. We have previously shown that the αvβ5 integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) regulates cellular uptake of fatty acids. In this work, we evaluated the impact of MFGE8 on glucose homeostasis. We show that acute blockade of the MFGE8/β5 pathway enhances while acute augmentation dampens insulin-stimulated glucose uptake. Moreover, we find that insulin itself induces cell-surface enrichment of MFGE8 in skeletal muscle, which then promotes interaction between the αvβ5 integrin and the insulin receptor leading to dampening of skeletal-muscle insulin receptor signaling. Blockade of the MFGE8/β5 pathway also enhances hepatic insulin sensitivity. Our work identifies an autoregulatory mechanism by which insulin-stimulated signaling through its cognate receptor is terminated through up-regulation of MFGE8 and its consequent interaction with the αvβ5 integrin, thereby establishing a pathway that can potentially be targeted to improve insulin sensitivity.

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Context: Experiencing early-life adversity plays a key role in the development of mood disorders in adulthood. Experiencing adversities during early life period negatively affects brain development. Sex steroids such as progesterone affect the brain structure and functions and subsequently affects behaviour. Objective: We assess the antidepressant-like effect of progesterone in a mouse model of maternal separation (MS) stress, focussing on its anti-neuroinflammatory and antioxidative effects. Materials and methods: NMRI mice were treated with progesterone (10, 50, and 100 mg/kg, i.p., respectively) for 14 days. Valid behavioural tests including forced swimming test (FST), splash test and open field test (OFT) were used. Quantitative reverse transcription-PCR (qRT-PCR) was used for evaluation of genetic expression in the hippocampus. Antioxidant capacity was assessed by the FRAP method and the level of malondialdehide by TBA. Results: MS provoked depressive-like behaviour in mice. Treatment of MS mice with progesterone increased the grooming activity time in the splash test and decreased the immobility time in the FST. In addition, progesterone decreased the expression of inflammatory genes related to neuroinflammation (IL-1b, TNF-a, TLR4 and NLRP3) as well as increased the antioxidant capacity and decreased the lipid peroxidation (MDA) in the hippocampus. Discussion and Conclusion: Administration of progesterone significantly mitigated the negative effects of MS on behaviours relevant to depressive-like behaviour as well as attenuated neuro-immune response and oxidative stress in the hippocampus of MS mice. In this context, we conclude that progesterone, at least partially, via attenuation of oxidative stress and neuroinflammation, exerts antidepressant-like effects.

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Mitochondrial dysfunction is one of the main causative factors in a wide variety of complications such as neurodegenerative disorders, ischemia/reperfusion, aging process, and septic shock. Decrease in respiratory complex activity, increase in free radical production, increase in mitochondrial synthase activity, increase in nitric oxide production, and impair in electron transport system and/or mitochondrial permeability are considered as the main factors responsible for mitochondrial dysfunction. Melatonin, the pineal gland hormone, is selectively taken up by mitochondria and acts as a powerful antioxidant, regulating the mitochondrial bioenergetic function. Melatonin increases the permeability of membranes and is the stimulator of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. It also acts as an inhibitor of lipoxygenase. Melatonin can cause resistance to oxidation damage by fixing the microsomal membranes. Melatonin has been shown to retard aging and inhibit neurodegenerative disorders, ischemia/reperfusion, septic shock, diabetes, cancer, and other complications related to oxidative stress. The purpose of the current study, other than introducing melatonin, was to present the recent findings on clinical effects in diseases related to mitochondrial dysfunction including diabetes, cancer, gastrointestinal diseases, and diseases related to brain function.

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