Garlic exosome-like nanoparticles reverse high-fat diet induced obesity via the gut/brain axis

Abstract

Background: Obesity is becoming a global epidemic and reversing the pathological processes underlying obesity and metabolic co-morbidities is challenging. Obesity induced chronic inflammation including brain inflammation is a hallmark of obesity via the gut-brain axis. The objective of this study was to develop garlic exosome-like nanoparticles (GaELNs) that inhibit systemic as well as brain inflammatory activity and reverse a HFD induced obesity in mice. Methods: GELNs were isolated and administrated orally into HFD fed mice. GaELNs were fluorescent labeled for monitoring their in vivo trafficking route after oral administration and quantified the number particles in several tissues. The brain inflammation was determined by measuring inflammatory cytokines by ELISA and real-time PCR. Mitochondrial membrane permeability of microglial cells was determined using JC-10 fluorescence dye. The in vivo apoptotic cell death was quantified by TUNEL assay. The brain metabolites were identified and quantified by LC-MS analysis. Memory function of the mice was determined by several memory functional analysis. The effect of GaELNs on glucose and insulin response of the mice was determined by glucose and insulin tolerance tests. c-Myc localization and interaction with BASP1 and calmodulin was determined by confocal microscopy. Results: Our results show that GaELNs is preferentially taken up microglial cells and inhibits the brain inflammation in HFD mice. GaELN phosphatidic acid (PA) (36:4) is required for the uptake of GaELNs via interaction with microglial BASP1. Formation of the GaELNs/BASP1 complex is required for inhibition of c-Myc mediated expression of STING. GaELN PA binds to BASP1, leading to inhibition of c-Myc expression and activity through competitively binding to CaM with c-Myc transcription factor. Inhibition of STING activity leads to reducing the expression of an array of inflammatory cytokines including IFN-γ and TNF-α. IFN-γ induces the expression of IDO1, which in turn the metabolites generated as IDO1 dependent manner activate the AHR pathway that contributes to developing obesity. The metabolites derived from the GaELNs treated microglial cells promote neuronal differentiation and inhibit mitochondrial mediated neuronal cell death. GaELNs treated HFD mice showed improved memory function and increased glucose tolerance and insulin sensitivity in these mice. Conclusion : Collectively, these results demonstrate how nanoparticles from a healthy diet can inhibit unhealthy high-fat diet induced brain inflammation and reveal a link between brain microglia/diet to brain inflammatory disease outcomes via diet-derived exosome-like nanoparticles.

Emergence of Edible Plant-Derived Nanovesicles as Functional Food Components and Nanocarriers for Therapeutics Delivery: Potentials in Human Health and Disease

“…Oat bran meal was dissolved in PBS and then incubated in a 37 °C water bath for 30 min for supernatant collection and subsequent centrifugation [ 29 ]. Root vegetables, such as carrot [ 30 ], garlic [ 31 , 32 , 33 ], ginger [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ], ginseng [ 42 , 43 ], and turmeric [ 44 ], and leafy vegetables including cabbage [ 45 ], were prepared similarly to fruits by blending them with or without additional PBS pre- or post-grinding.…”

“…Xu et al showed that oral administration of DiR labeled oat-derived nanovesicles resulted in signal detection in the brain at 1 h post gavage with a gradual decrease after 6 h and preferential uptake by microglial cells in the brain [ 29 ]. Similarly, Sundaram et al showed that garlic-derived nanovesicles given orally traveled to the brain approximately at the same amount as the liver and intestine [ 33 ]. Specifically, brain microglial cells but not neuronal cells selectively took the garlic-derived nanovesicles [ 33 ].…”

“…Similarly, Sundaram et al showed that garlic-derived nanovesicles given orally traveled to the brain approximately at the same amount as the liver and intestine [ 33 ]. Specifically, brain microglial cells but not neuronal cells selectively took the garlic-derived nanovesicles [ 33 ].…”

Emerging Role of Edible Exosomes-Like Nanoparticles (ELNs) as Hepatoprotective Agents

“…Among which PA has shown interaction with mammalian target of rapamycin (mTOR) which results in cell growth and proliferation 31 and since it is mitosis phospholipid, and highly fusogenic with calcium presence which induces inter-vesicular fusion 32 . Contains high PA composition, garlic ELNs also mostly taken by microglial cells by forming garlic ELN/BASP1 complex, helps in mitigating brain inflammation 33 . Based on these studies further question has been raised whether these phospholipids along with their presence and composition are having any role in getting into their target cells.…”

“…Garlic ELNs taken up the microglial cells and inhibits brain inflammation. They help in the downregulation of cMyc gene mediated expression of STING activity which leads to reduce the activities of pro-inflammatory cytokines including IFN-γ and TNF-α 33 . Whereas IFN-γ- IDO1 interaction that usually activates the AHR pathway contributes to the attenuation of development of obesity.…”