A single gene deficiency (Timp3) affects the regulation of nutrition and metabolism – Harnessing the gut microbiome

Abstract

The prevalence of metabolic syndrome (MetS) (defined as the clustering of insulin resistance, obesity, and hypertension) has sharply increased since the late 20th century and continues to rise into the present day. Metabolic syndrome leads to the development of many chronic diseases such as Type 2 Diabetes and cardiovascular diseases, the likelihood of which increases with age. Increased accessibility to high-volume, calorie dense, and highly processed foods is often pointed as the culprit for this event. However, these multifactorial conditions are known to have many genetic components and are highly influenced by the gut microbiome. As worldwide obesity and MetS rates continue to grow, the need for novel therapies to combat the problem become evermore important. This PhD project aimed to investigate the role of the gut microbiome and the extracellular matrix (ECM), via the protein TIMP3, in diet-induced obesity (DIO) and ageing mouse models.
Timp3-/- DIO mice gut had decreased abundance of short-chain fatty acid (SCFA) producing Lachnospiraceae bacteria, alongside decreased circulating butyrate. These mice also exhibited dysregulated energy metabolism which lead to changes in adipose tissue storage and development of obesity.
Female Timp3-/- mice have impaired aorta constriction and relaxation response, in part due to aberrant extracellular matrix remodelling and dysfunctional endothelial and vascular smooth muscle cell signalling.
This study presents a model of MetS and CVD development, via deletion of Timp3, within mice. The findings suggest that MetS development in the Timp3-/- mouse is in part due to changes in the gut microbiota composition.

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Identifiers

ORCID for Sylvia Pender: orcid.org/0000-0001-6332-0333

ORCID for David Cleary: orcid.org/0000-0003-4533-0700

ORCID for Felino Cagampang: orcid.org/0000-0003-4404-9853

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