Cellular retinoic acid binding protein 1 protects mice from high-fat diet-induced obesity by decreasing adipocyte
Yi-Wei Lin1, Sung Wook Park1, Yu-Lung Lin1
1Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
Objectives:
Obesity, an emerging global health issue, involves numerous factors; understanding its underlying mechanisms for prevention and therapeutics is urgently needed. Cellular retinoic acid binding protein 1 (Crabp1) knockout (CKO) mice exhibit an obese phenotype under normal diet (ND) feedings, which prompted us to propose that Crabp1 could play a role in modulating adipose tissue development/homeostasis. Studies were designed to elucidate the underlying mechanism of Crabp1's action in reducing obesity.
Subjects/Methods:
In animal studies, 6 weeks old male wild type and CKO mice were fed with ND or high-fat diet (HFD) for 10 weeks. Body weight and food intake were regularly monitored. Glucose tolerance test and biological parameters of plasma (glucose and insulin levels) were measured after 10 weeks of ND vs. HFD feedings. Visceral adipose tissues were collected for histological and molecular analyses to determine affected signaling pathways. In cell culture studies, the 3T3L1 adipocyte differentiation model was used to examine and validate relevant signaling pathways.
Results:
CKO mice, compared to WT mice, gained more body weight, exhibited more elevated fasting plasma glucose levels, and developed more severe impaired glucose tolerance under both ND and HFD. Histological examination revealed readily increased adipocyte hypertrophy and adipose tissue inflammation under HFD feedings. In 3T3L1 adipocytes, Crabp1 silencing enhanced extracellular signal-regulated kinase 1/2 (ERK1/2) activation, accompanied by elevated markers and signaling pathways of lipid accumulation and adipocyte hypertrophy.
Conclusions:
This study identifies Crabp1's physiological role against the development of obesity. The protective function of CRABP1 is likely attributed to its classically proposed (canonical) activity as a trap for RA, which will reduce RA availability, thereby dampening RA-stimulated ERK1/2 activation and adipocyte hypertrophy. The results suggest Crabp1 as a potentially new therapeutic target in managing obesity and metabolic diseases.
Insights
Cellular retinoic acid binding protein 1 (Crabp1) plays a protective role against obesity. Its absence in knockout mice leads to increased weight gain and impaired glucose tolerance, suggesting Crabp1 as a therapeutic target.
Area of Science:
- Metabolic disease research
- Obesity mechanisms
- Cellular biology
Background:
- Obesity is a growing global health concern requiring novel therapeutic strategies.
- Cellular retinoic acid binding protein 1 (Crabp1) knockout (CKO) mice display an obese phenotype, indicating a potential role in adipose tissue regulation.
Purpose of the Study:
- To investigate the underlying mechanisms by which Crabp1 influences obesity development.
- To elucidate the physiological function of Crabp1 in modulating adipose tissue homeostasis and metabolic health.
Main Methods:
- Comparative analysis of wild-type and CKO mice fed normal or high-fat diets, monitoring weight, food intake, and glucose metabolism.
- Histological and molecular analyses of visceral adipose tissue.
- In vitro studies using 3T3L1 adipocytes to validate signaling pathways involved in lipid accumulation and hypertrophy.
Main Results:
- CKO mice exhibited greater weight gain, elevated fasting glucose, and worsened glucose intolerance compared to wild-type mice under both dietary conditions.
- Histological analysis revealed increased adipocyte size and inflammation in CKO mice, particularly under high-fat diet.
- Crabp1 silencing in adipocytes promoted ERK1/2 activation and markers of lipid accumulation and hypertrophy.
Conclusions:
- Crabp1 demonstrates a physiological role in preventing obesity development.
- Crabp1's protective effect is linked to its canonical function of binding retinoic acid (RA), reducing RA-driven ERK1/2 activation and adipocyte hypertrophy.
- Crabp1 emerges as a potential therapeutic target for obesity and associated metabolic disorders.
Related Concept Videos
02:42Acidity of 1-Alkynes
The acidic strength of hydrocarbons follows the order: Alkynes > Alkenes > Alkanes. The strength of an acid is commonly expressed in units of pKa — the lower the pKa, the stronger the acid. Among the hydrocarbons, terminal alkynes have lower pKa values and are, therefore, more acidic. For example, the pKa values for ethane, ethene, and acetylene are 51, 44, and 25, respectively, as shown here.
02:18The Equilibrium Binding Constant and Binding Strength
01:27Decreasing Function
01:24Obesity
02:40Ligand Binding Sites
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
01:49Conserved Binding Sites
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...