Four-and-a-half LIM domain protein 2 (FHL2) deficiency protects mice from diet-induced obesity and high FHL2 expression marks human obesity

Abstract

Four-and-a-half LIM domain protein 2 (FHL2) Energy metabolism Energy expenditure Glucose uptake Lipid uptake White adipose tissue (WAT) Browning of WAT Objective: Four-and-a-Half-LIM-domain-protein 2 (FHL2) modulates multiple signal transduction pathways but has not been implicated in obesity or energy metabolism. In humans, methylation and expression of the FHL2 gene increases with age, and high FHL2 expression is associated with increased body weight in humans and mice. This led us to hypothesize that FHL2 is a determinant of diet-induced obesity. Methods: FHL2-deficient (FHL2−/−) and wild type male mice were fed a high-fat diet. Metabolic phenotyping of these mice, as well as transcriptional analysis of key metabolic tissues was performed. Correlation of the expression of FHL2 and relevant genes was assessed in datasets from white adipose tissue of individuals with and without obesity. Results: FHL2 Deficiency protects mice from high-fat diet-induced weight gain, whereas glucose handling is normal. We observed enhanced energy expenditure, which may be explained by a combination of changes in multiple tissues; mild activation of brown adipose tissue with increased fatty acid uptake, increased cardiac glucose uptake and browning of white adipose tissue. Corroborating our findings in mice, expression of FHL2 in human white adipose tissue positively correlates with obesity and negatively with expression of browning-associated genes. Conclusion: Our results position FHL2 as a novel regulator of obesity and energy expenditure in mice and human. Given that FHL2 expression increases during aging, we now show that low FHL2 expression associates with a healthy metabolic state.

How (Epi)Genetic Regulation of the LIM-Domain Protein FHL2 Impacts Multifactorial Disease

“…A similar pattern was observed in adipose tissue, with enhanced DNA methylation of the FHL2 gene resulting in higher expression levels [43]. FHL2 expression in adipose tissue correlates with increased body mass, and it has recently been demonstrated that FHL2-KO mice are resistant to weight gain involving increased 'browning' of white adipose tissue [16].…”

“…There is an emerging focus on FHL2 function in the context of metabolism [16,68], which is also reflected by the observation that rs3087523 and rs186607487 are associated with body mass index (BMI) and fat body mass, respectively (Table 1) [60][61][62]. In line with this observation, FHL2-deficient mice gain less weight than their wild-type littermates in response to a high-fat diet [16]. In the latter study, 'browning' of white adipocytes was observed in the mice upon FHL2 deficiency.…”

“…Similar changes in gene expression were observed in human white adipose tissue. In humans, increased FHL2 expression is also associated with decreased expression of a number of the so-called 'browning genes', such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1a), cardiolipin synthase 1 (CRLS1), sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor gamma (PPARG), and bone-morphogenic protein 7 (BMP7) [16]. Of note, the variants rs3087523 and rs62155873 are in high linkage disequilibrium (LD) and are both associated with BMI in the same study.…”

“…FHL2 is expressed most abundantly in the heart, blood vessels, ovary, and skeletal muscle, and to a lesser extent in several other organs [5][6][7][8]. FHL2 expression and function have been studied in a number of diseases, including various types of cancer [9][10][11][12], cardiovascular disease [5,6,8,[13][14][15], and overall metabolism [16]. At present, information regarding the exact regulation of FHL2 expression is limited [17,18].…”

The titin N2B and N2A regions: biomechanical and metabolic signaling hubs in cross-striated muscles

“…FHL2 has been suggested to tether phosphofructokinase, adenylate kinase and muscle creatine kinase to the sarcomeric I-band in cardiomyocytes (Lange et al 2002 ), and to bind to pyruvate dehydrogenase (Pdhb) (Huttlin et al 2015 ). Loss of FHL2 in mice leads to reduced weight gain by diet-induced obesity, higher energy expenditure, browning of white adipose tissue and enhanced glucose uptake and consumption of the heart (Clemente-Olivo et al 2021 ). Analysis of mRNA expression in the heart suggests significant modulation of the X nuclear receptor (Lxr)/retinoid X receptor (Rxr), Mapk and Erk signaling and glucose metabolism pathways.…”