Diet-dependent function of the extracellular matrix proteoglycan Lumican in obesity and glucose homeostasis

G Wolff,A.E Taranko,I Meln,J Weinmann,T Sijmonsma,S Lerch,D Heide,A.T Billeter,D Tews,D Krunic,P Fischer-Posovszky,B.P Müller-Stich,S Herzig,D Grimm,M Heikenwälder,W.W Kao,A Vegiopoulos

doi:10.1016/j.molmet.2018.10.007

Abstract

ObjectiveExtracellular matrix remodeling is required for adipose expansion under increased caloric intake. In turn, inhibited expandability due to aberrant collagen deposition promotes insulin resistance and progression towards the metabolic syndrome. An emerging role for the small leucine-rich proteoglycan Lumican in metabolically driven nonalcoholic fatty liver disease sparks an interest in further understanding its role in diet-induced obesity and metabolic complications. MethodsWhole body ablation of Lumican (Lum−/−) gene and adeno-associated virus-mediated over-expression were used in combination with control or high fat diet to assess energy balance, glucose homeostasis as well as adipose tissue health and remodeling. ResultsLumican was found to be particularly enriched in the stromal cells isolated from murine gonadal white adipose tissue. Likewise murine and human visceral fat showed a robust increase in Lumican as compared to fat from the subcutaneous depot. Lumican null female mice exhibited moderately increased fat mass, decreased insulin sensitivity and increased liver triglycerides in a diet-dependent manner. These changes coincided with inflammation in adipose tissue and no overt effects in adipose expandability, i.e. adipocyte formation and hypertrophy. Lumican over-expression in visceral fat and liver resulted in improved insulin sensitivity and glucose clearance. ConclusionsThese data indicate that Lumican may represent a functional link between the extracellular matrix, glucose homeostasis, and features of the metabolic syndrome.

Highlights

Adipose tissue expansion in the face of caloric excess initiates concomitant processes including angiogenesis, inflammation, and extracellular matrix (ECM) remodeling [1,2]
Female mice maintained on control diet (CD) for 8 weeks had significantly higher Lum mRNA levels in gonadal white adipose tissue compared to subcutaneous inguinal white adipose tissue or interscapular brown adipose tissue (BAT) (Figure 1A)
When mice were housed on high-fat diet (HFD) for 10 weeks, Lum expression was increased in female gonadal white adipose tissue (gWAT) but not inguinal white adipose tissue (iWAT) (Figure 1B)

Summary

Introduction

Adipose tissue expansion in the face of caloric excess initiates concomitant processes including angiogenesis, inflammation, and extracellular matrix (ECM) remodeling [1,2]. Persistent adipose growth promotes obesity, progression towards the metabolic syndrome, and type-2 diabetes. The regulation of insulin sensitivity as a pathogenic factor in the metabolic syndrome represents an important target driving current and future therapeutic treatments [1,3,4]. The “expandability hypothesis” suggests that fat accumulation in organs outside of the adipose tissue leads to cell death, inflammation, and insulin resistance providing one explanation for obesity-driven insulin resistance as well as insulin-sensitive obesity [4e6]. Remodeling the ECM in adipose tissue requires reciprocal processes of depositing new matrix proteins, mainly collagens, and breaking down via proteases such as matrix metalloproteinases (MMPs) [4]

Methods

Results

Conclusion