Diet-induced weight loss in obese/diabetic mice normalizes glucose metabolism and promotes functional recovery after stroke

Abstract

Background Post-stroke functional recovery is severely impaired by type 2 diabetes (T2D). This is an important clinical problem since T2D is one of the most common diseases. Because weight loss-based strategies have been shown to decrease stroke risk in people with T2D, we aimed to investigate whether diet-induced weight loss can also improve post-stroke functional recovery and identify some of the underlying mechanisms. Methods T2D/obesity was induced by 6 months of high-fat diet (HFD). Weight loss was achieved by a short- or long-term dietary change, replacing HFD with standard diet for 2 or 4 months, respectively. Stroke was induced by middle cerebral artery occlusion and post-stroke recovery was assessed by sensorimotor tests. Mechanisms involved in neurovascular damage in the post-stroke recovery phase, i.e. neuroinflammation, impaired angiogenesis and cellular atrophy of GABAergic parvalbumin (PV)+ interneurons were assessed by immunohistochemistry/quantitative microscopy. Results Both short- and long-term dietary change led to similar weight loss. However, only the latter enhanced functional recovery after stroke. This effect was associated with pre-stroke normalization of fasting glucose and insulin resistance, and with the reduction of T2D-induced cellular atrophy of PV+ interneurons. Moreover, stroke recovery was associated with decreased T2D-induced neuroinflammation and reduced astrocyte reactivity in the contralateral striatum. Conclusion The global diabetes epidemic will dramatically increase the number of people in need of post-stroke treatment and care. Our results suggest that diet-induced weight loss leading to pre-stroke normalization of glucose metabolism has great potential to reduce the sequelae of stroke in the diabetic population.

Exploring the hub mechanisms of ischemic stroke based on protein-protein interaction networks related to ischemic stroke and inflammatory bowel disease

“…PPRF8 (pre-mRNA processing factor 8), a core component of the spliceosome, is an important mediator of hypoxia-induced mitosis 52 , and a high-fat diet upregulates the expression of genes related to the spliceosome 53 , increasing the risk of ischemic stroke. Adjusting the diet may enhance functional recovery after stroke by modulating insulin resistance and normalizing glucose metabolism 54 .…”

The Pre-Stroke Induction and Normalization of Insulin Resistance Respectively Worsens and Improves Functional Recovery

“…To investigate mechanisms of neuroplasticity, we focused our studies on striatal cholinergic ChAT + interneurons, since these cells coordinate the firing of medium spiny neurons that in turn regulate motor output [ 38 ] and also regulate stroke recovery [ 39 ]. Other interneurons, such as those positive for Parvalbumin and Somatostatin, have been recently investigated in other studies from our group [ 17 , 25 , 26 , 29 , 34 ]. We recorded an overall increased number of ChAT + interneurons in IR-HG and IR-NG sham-operated mice versus healthy CTRL mice, likely indicating an upregulation of ChAT expression, making more cells detectable by IHC.…”

“…Moreover, insulin signaling in hypothalamic astrocytes controls CNS glucose sensing and systemic glucose metabolism via the regulation of glucose uptake across the BBB [ 64 ]. In relation to stroke recovery, we also recently showed that HFD feeding results in reduced astrocyte reactivity in association with impaired recovery [ 17 ]. It is therefore plausible that impaired insulin signaling in astrocytes plays an important role in decreased recovery.…”

“…Similar to hyperglycemia, IR has been associated with poor stroke outcomes [ 14 , 16 ]. Moreover, we recently showed that a dietary change leading to weight loss before stroke improved stroke recovery and this effect occurred in association with the pre-stroke normalization of IR [ 17 ], pointing towards the detrimental role of IR in impairing stroke recovery in T2D. However, the causative role of IR in impaired stroke recovery has not yet been established, and interventional studies aiming to normalize IR pre-stroke in the preventive perspective to limit stroke sequelae in T2D individuals are lacking.…”

“…However, it is essentially impossible to individually determine the effects of these conditions on stroke clinically since both are present in T2D patients. Furthermore, the detrimental effects of T2D on some self-repairing mechanisms during the stroke recovery phase, e.g., neuroplasticity [ 25 , 26 , 27 ], stroke-induced neurogenesis [ 25 , 27 ], stroke-induced oligodendrogenesis and white matter repair [ 27 , 28 ], vascular function [ 29 , 30 ] (also reviewed in [ 31 ]) and neuroinflammation [ 17 , 32 , 33 , 34 ] (reviewed in [ 35 ]), have been recently demonstrated. However, the specific effects of hyperglycemia and IR on these cellular mechanisms are essentially unknown due to the very close interplay of these two factors during the diabetic disease.…”