NOD1 deficiency promotes an imbalance of thyroid hormones and microbiota homeostasis in mice fed high fat diet

Abstract

The contribution of the nucleotide-binding oligomerization domain protein NOD1 to obesity has been investigated in mice fed a high fat diet (HFD). Absence of NOD1 accelerates obesity as early as 2 weeks after feeding a HFD. The obesity was due to increases in abdominal and inguinal adipose tissues. Analysis of the resting energy expenditure showed an impaired function in NOD1-deficient animals, compatible with an alteration in thyroid hormone homeostasis. Interestingly, free thyroidal T4 increased in NOD1-deficient mice fed a HFD and the expression levels of UCP1 in brown adipose tissue were significantly lower in NOD1-deficient mice than in the wild type animals eating a HFD, thus contributing to the observed adiposity in NOD1-deficient mice. Feeding a HFD resulted in an alteration of the proinflammatory profile of these animals, with an increase in the infiltration of inflammatory cells in the liver and in the white adipose tissue, and an elevation of the circulating levels of TNF-α. In addition, alterations in the gut microbiota in NOD1-deficient mice correlate with increased vulnerability of their ecosystem to the HFD challenge and affect the immune-metabolic phenotype of obese mice. Together, the data are compatible with a protective function of NOD1 against low-grade inflammation and obesity under nutritional conditions enriched in saturated lipids. Moreover, one of the key players of this early obesity onset is a dysregulation in the metabolism and release of thyroid hormones leading to reduced energy expenditure, which represents a new role for these hormones in the metabolic actions controlled by NOD1.

NOD1-Targeted Immunonutrition Approaches: On the Way from Disease to Health

“…Our group and others [ 57 , 58 , 59 , 60 ] have described a prominent role for NOD1 in the leading cause of death worldwide: cardiovascular diseases (CVDs). NOD1 has been shown to contribute to atherogenesis, both in early and advanced disease.…”

“…NOD1 deletion in Apoe −/− mice, one of the most commonly used animal models of atherogenesis, reduces the burden of the disease and the accumulation of leukocytes within the lesions, especially monocytes and neutrophils. Endothelial NOD1 activated by PGNs or oxidized LDLs (oxLDLs, important within diet and lipid sources), leads to overexpression of VCAM-1 and subsequent adhesion of leukocytes to athero-prone vessels [ 57 , 58 , 59 , 60 ]. When atherogenesis progresses, there is a risk of atherothrombosis and acute coronary syndromes, triggered by unstable plaque rupture, cell necrosis, hyperinflammation, and decreased collagen content.…”

“…In these circumstances, cells such as macrophages and smooth muscle cells play a critical role since they proliferate, undergo apoptosis, and form foam cells within the plaque. NOD1 is involved in all these processes that contribute to the vulnerability of atheromas [ 58 , 61 ]. Cardiac dysfunction, impaired excitation–contraction coupling, and Ca 2+ handling have also been associated with NOD1 [ 62 ].…”

“…In addition, the thyroid gland is regulated by the nutritional status and other signals such as leptin or appetite-controlling peptides. Therefore, there is a need for an immunonutrition approach for thyroid dysfunctions involving or not involving NOD1 [ 41 , 58 ].…”

Bacteroides Uniformis CECT 7771 Alleviates Inflammation Within the Gut-adipose Tissue Axis, Involving TLR5 Signaling, in Diet-Induced Obese Mice

“…Processing of samples for gut microbiota analysis was carried out according to the methods described in González-Ramos 49 . Fecal samples from individual mice from each experimental group were collected at the end of the intervention and were immediately frozen in liquid nitrogen and stored at -80°C until processing.…”