Role of ECM in the Brain‐Gut Connection

Abstract

We sought to determine the role of extracellular matrix (ECM) proteoglycans on regulating brain function and cell metabolism. In the first series of studies, we used dietary fructose to perturbate metabolism based on evidence that fructose is a major contributor to the epidemic of diabetes and obesity. Our transcriptomic studies (Meng et al, EBiomed, 157(7), 2016) showed that the gene for the proteoglycan biglycan (Bgn) occupies a central position in a network of genes receptive to the action of fructose in the hypothalamus (main brain center of metabolic control). We pursued studies further and exposed male biglycan knockout mice (Bgn0/-) to fructose for 7 weeks, and results showed that the Bgn0/- gene perturbation compensated for a decrement in learning and memory performance in mice exposed to fructose (Ying et al., BBADIS, 1864(12) 2018). Learning and memory performance was consistent with an attenuation of the action of fructose on hippocampal plasticity markers CREB and BDNF. Bgn siRNA treatment abolished the effects of fructose on CREB and BDNF levels, in conjunction with reducing a fructose-related increase in Bgn protein. In addition, fructose consumption perturbed the systemic metabolism of glucose and lipids, that were also altered in the Bgn0/ mice. Transcriptomic profiling of hypothalamus, hippocampus, and liver supported the regulatory action of Bgn on key molecular pathways involved in metabolism, immune response, and neuronal plasticity. Overall results underscore the tissue-specific role of the extracellular matrix in the regulation of metabolism and brain function, and support Bgn as a key modulator of the impact of fructose across body and brain. In separate studies, we found that the gene for the proteoglycan fibromodulin (Fmod) controls a network of genes responsive to the action of brain trauma (EBiomed, 184(16) 2017). The action of Fmod (42-80 KDa) on the brain is poorly understood and rather known for affecting fibrillogenesis, cell adhesion, cytokine activity in the periphery. We found that deletion of Fmod gene mitigated the TBI-related increase in the pro-inflammatory marker toll like receptor 4 (TLR4), and attenuated a reduction in cell metabolic markers PGC1alpha and cytochrome oxidase II (COII), in the mouse hypothalamus after TBI. The latter suggests that Fmod deletion can protect against the cell metabolic crisis observed after TBI. In addition, given the regulatory role of the hypothalamus on peripheral metabolism, we sought to determine the effects of Fmod genetic deletion on the homeostasis of lipids in the liver on mice exposed to TBI. Results showed that the deletion of the Fmod gene protected against the action of brain trauma on key lipids and the levels of fatty acid synthase (FAS), a major lipogenic enzyme commonly involved in fatty acid processing. These results suggest a potential effect of Fmod on brain trauma outcome in brain and periphery.