Amelioration of hippocampal dysfunction by adipose tissue‐targeted stem cell transplantation in a mouse model of type 2 diabetes

Abstract

There is growing evidence that type 2 diabetes or insulin resistance is linked to cognitive impairment. We recently confirmed altered lipid composition, down‐regulation of insulin receptor expression and impaired basal synaptic transmission in the hippocampus of our transgenic murine model of adipocyte insulin resistance (AtENPP1‐Tg). Here we evaluated whether the correction of adipose tissue dysfunction [via the subcutaneous transplantation of mesenchymal stem cells (MSC)] can improve the hippocampal synaptic transmission in AtENPP1‐Tg mice versus their wildtype littermates. Animals were simply randomized to receive MSC, then weighed weekly for 12 weeks. At euthanasia, we assessed leptin in the collected serum and hippocampal synaptic high‐frequency stimulation long‐term potentiation (HFS‐LTP) using brain slices. MSC transplantation normalized AtENPP1‐Tg body and epididymal fat weights and was associated with increased leptin levels, a sign of adipocyte maturation. More importantly, transplantation restored the deficiency observed in AtENPP1‐Tg HFS‐LTP, the cellular readout of memory. Our results further corroborate the role of adipocyte maturation arrest in adipose tissue and highlight a role for the adipose tissue in modulating hippocampal cellular mechanisms. Further studies are warranted to explore the mechanisms for the MSC‐induced improvement of hippocampal HFS‐LTP.

Near-infrared light reduces glia activation and modulates neuroinflammation in the brains of diet-induced obese mice

“…To study HFD/obesity-induced neuroinflammation we employed the DIO mouse model, which is a wild-type mouse chronically fed an HFD 106 , 107 . Notably, the DIO mouse model develops obesity, hyperglycemia, insulin resistance, decreased neurogenesis, impaired synaptic transmission 108 , 109 , and neuroinflammation. All of these events are also present in dementia, so this model affords the unique opportunity to study obesity-induced CNS deficits 110 .…”

Adipose Tissue-Derived Stem Cells from Type 2 Diabetics Reveal Conservative Alterations in Multidimensional Characteristics

“…However, systematic and detailed dissection of T2DM-ASCs both at the cellular and molecular levels is fundamental and prerequisite to discover the proofs on pathogenesis of diabetes mellitus ( 7 , 19 ). For instance, Wang et al ( 23 ) and Krishnan et al ( 34 ) reported that intravenous injection of ASCs was sufficient to improve insulin sensitivity and alleviate β cell death and even ameliorate hippocampal dysfunction of T2DM percipient mice, respectively. Congruously, we currently verified that MSCs participated in the restorative process of dysfunctional type 2 diabetic islets by reversing β cell dedifferentiation, yet the underling pathogenesis of T2DM-ASCs involved in the progression and efficacy still need further systematic and in-depth research ( 23 ).…”

Phospholipase D1 Attenuation Therapeutics Promotes Resilience against Synaptotoxicity in 12-Month-Old 3xTg-AD Mouse Model of Progressive Neurodegeneration

“…Our standard protocol was used as previously described [ 13 , 14 , 15 , 42 , 76 , 77 , 147 , 148 ]. Briefly, mice were deeply anesthetized with isoflurane and transcardially perfused with ~30 mL of room temperature carbogenated (95% O 2 and 5% CO 2 gas mixture) NMDG-artificial cerebrospinal fluid (aCSF) (in mM-93 N-Methyl-D-Gluconate, 2.5 KCl, 1.2 NaH 2 PO 4 , 30 NaHCO 3 , 20 C 8 H 18 N 2 O 4 S, 25 C 6 H 12 O 6 , 5 C 6 H 7 O 6 Na, 2 CH 4 N 2 S, 3 C 3 H 3 NaO 3 , 10 MgSO 4 ,7H 2 O, 0.5 CaCl 2 ,2H 2 O, 12 C 5 H 9 NO 3 S, pH 7.4) and sliced using Compresstome VF-300 (Precisionary Instruments, Greenville, NC, USA) in carbogenated NMDG-aCSF to obtain 350 μm transverse brain sections.…”

“…Field potentials were recorded in CA1 stratum radiatum using a Ag/AgCl bridge with CV7B headstage (Molecular Devices, Sunnyvale, CA, USA) located ~1–2 mm from the stimulating electrode. LTP was induced using a high frequency stimulation protocol (3 × 100 Hz, 20 s) as previously described [ 13 , 14 , 15 , 42 , 76 , 77 , 147 ]. LTD was induced using a low frequency stimulation protocol (900 × 1 Hz).…”