In our previous article, we provided an Introduction to Murine Models of Obesity (Part 1): LEP/LEPR Classic Pathway Model. In this edition, we will delve into non-LEP/LEPR genetic mouse models for obesity research.

The Mechanisms of Obesity

Genetic obesity is primarily caused by abnormalities in the leptin signaling pathway molecules. Animal models based on this pathway's genes, mainly LEP and LEPR, are widely used in obesity research. However, apart from LEP/LEPR, there are other leptin pathways and regulatory pathway genes that are also closely associated with the development of obesity and can be used for constructing obesity models and studying mechanisms.

Figure 1. Leptin Signaling Pathway and Regulatory Pathways Regulating Body Weight [1]

β-Adrenergic Receptor (βAR) Family Pathway Deficiency Model

As ob/ob mice (aka B6 ob, ob)  homozygous for the obese spontaneous mutation, Lepob  have been the primary obesity model over the last century, studies revealed that the mice had defects in the β-adrenergic receptor (βAR) signaling. This manifested as a lack of lipolysis (fat breakdown) and impaired non-shivering thermogenesis. However, it was found that the activities of the two subtypes, β1AR and β2AR, showed no significant changes. Subsequent research gradually led to the discovery of the highly expressed β3AR subtype in adipose tissue, which allowed for a more precise classification and definition of these three subtypes.[2] In ob/ob mice, the expression of β3AR is completely absent, and β1AR also significantly decreases, suggesting a potential role of the βAR family in inhibiting adipogenesis (fat development) and subsequent obesity.[3]

Figure 2. Complete Absence of β3AR Expression in ob/ob Mice [3]

β-Adrenergic Receptor Subtypes: β1AR, β2AR, and β3AR

Thus far, research has revealed the distinct roles of the three βAR subtypes:

  • β1AR, responsible for regulating heart rate and myocardial contraction;
  • β2AR, associated with smooth muscle relaxation, insulin and glucagon secretion, and fat breakdown; and
  • β3AR, responsible for white fat lipolysis and brown fat thermogenesis in rodents.[4]

Figure 3. Different Expression Sites and Functions of the Three βAR Subtypes [4]

βAR Signaling Activity: Impacts on Obesity, Diabetes, Thermogenesis

β1AR, β2AR, and β3AR all inhibit obesity progression to varying degrees through different pathways. As the subtype with the highest content in adipose tissue, β3AR promotes fat tissue breakdown, skeletal muscle thermogenesis, increases muscle glucose uptake, and reduces hepatic glucose output, thus having anti-obesity and anti-diabetic effects. Conversely, mice with the knockout of β3AR (encoded by the Adrb3 gene) exhibit increased fat accumulation and food intake. High-fat feeding exacerbates the obesity phenotype, characterized by increased total body fat mass, decreased protein content, and reduced lean body mass, indicating that the loss of β3AR leads to the development of obesity.[5-6]

Figure 4. Compared to wild-type mice (○), β3AR-deficient mice (●) exhibit increased body weight and food intake.[5]

β1AR and β2AR are primarily responsible for regulating heart rate, myocardial contraction, smooth muscle relaxation, insulin and glucagon secretion, and fat breakdown. Their role in regulating obesity progression is not as prominent. However, β1AR and β2AR are also essential for diet-induced thermogenesis and play a crucial role in the body's defense against diet-induced obesity. Simultaneous deficiency of all three subtypes in mice results in more severe obesity, including abnormal brown adipose tissue morphology, reduced oxygen consumption, impaired adaptive thermogenesis, increased body weight, larger brown adipocyte size, and increased total fat mass.

Figure 5. Severe Obesity Phenotype in β1AR/β3AR/β2AR Knockout Mice (β-less)

5-Hydroxytryptamine/5-Hydroxytryptamine 2C Receptor Pathway Deficiency Model

5-Hydroxytryptamine (5-HT) plays complex and multifaceted roles in the human body, with its primary function being the regulation of emotions, while also contributing to the digestive system and the sleep-wake cycle. The 5-HT2C receptor is one of the subtypes of 5-HT receptors and plays a role alongside 5-HT in food intake and weight control.[8] Research from institutions such as Baylor College of Medicine has shown that mutations in the 5-HT2C receptor gene (HTR2C) play a significant role in obesity and maladaptive behavior. Some severely obese individuals carry rare loss-of-function (LOF) mutations in the HTR2C gene, and mice engineered to carry human HTR2C LOF mutations also develop hyperphagia and obesity.[9]

Figure 6. Mice Carrying Functional Loss Mutations in HTR2C Display Hyperphagic Obesity [9]

Furthermore, knocking out the expression of the
Htr2c gene in mice can also lead to overeating, hyperactivity, obesity, and a reduced response to anorexigenic 5-HT drugs. Re-expression of the Htr2c gene in POMC neurons can alleviate these symptoms.[10]

Figure 7. Increased Body Weight and Fat Percentage in HTR2C-KO Mice (2C null)

SHP2/ERK Signaling Deficiency Model

The effects of leptin on energy balance are achieved through the activation of the long form of leptin receptor (LR), which stimulates LR leading to phosphorylation of STAT3, activation of Src Homology 2 Containing Protein Tyrosine Phosphatase 2 (SHP2, aka SHPTP2), and insulin receptor substrate 2 (IRS2). SHP2 is encoded by the Ptpn11 gene and regulates cell growth, differentiation, and apoptosis by modulating signaling pathways such as RAS/ERK. SHP2 signaling in the central nervous system mediates leptin's anti-obesity effects. Research by Zhang et al. demonstrated that conditional Shp2 knockout (KO) mice in forebrain neurons (CaMKIIα-Cre; Shp2flox/flox) exhibit obesity and display several features of metabolic syndrome, highlighting the crucial role of SHP2 signaling in regulating energy balance and metabolism [11]. Similarly, deleting Ptpn11 in POMC neurons also leads to increased body weight and fat content in mice (Ptpn1loxP/loxP; POMC-Cre).[12]

Figure 8. Conditional Deletion of Shp2 in Forebrain Neurons Results in Severe Obesity in Mice [11]

Furthermore, by crossing pan-neuronal Cre mice (CRE3) with
Shp2flox/flox mice, the resulting mice with brain neuron-specific Shp2 deficiency exhibit even more severe obesity and diabetes. This condition is accompanied by various complications, including hyperglycemia, hyperinsulinemia, hyperleptinemia, insulin and leptin resistance, vasculitis, and diabetic nephropathy.[13] This provides valuable insights into the molecular mechanisms underlying human obesity, diabetes, and their associated complications.

Figure 9. Severe Obesity Phenotype in Pan-Neuronal Conditional Shp2 Knockout (KO) Mice [13]

JAK2-STAT3/STAT5 Signaling Deficiency Model

Leptin binds to LepRb, activating JAK2, which leads to phosphorylation of LepRb at the Tyr1138 and Tyr1077 sites. Phosphorylated Tyr1138 and Tyr1077 interact with Src homology 2 (SH2) domains, activating STAT3 and STAT5. Activated STAT3/STAT5 translocate to the cell nucleus and act as transcription factors to regulate the expression of target genes, thereby exerting a regulatory role. Disruption of STAT3 Tyr1138 in neurons leads to overeating and obesity in mice, similar to the phenotype observed in db/db mice [14]. Similarly, disruption of STAT5 Tyr1077 or conditional brain-specific Stat5 knockout in mice results in a phenotype of overeating and obesity.[15]

Figure 10. Brain-Specific Stat5 Knockout Leads to Increased Mouse Body Weight

Recommendations for Obesity Research Models

Mouse gene editing models play a crucial role in researching the mechanisms of obesity and other metabolic diseases, as well as in drug development and evaluation. Cyagen offers thousands of independently developed gene-edited mouse strains, including various gene knockout or conditional knockout mouse models such as LEP, LEPR, ADRB3, and SHP2. Moreover, we provide specialized customization services to meet your specific research needs, accelerating the progress of your studies.

Model Name Product Number Gene
B6-ob/ob C001368 LEP
B6-db/db C001291 LEPR
Adrb1-KO S-KO-16152 ADRB1
Adrb2-KO S-KO-00947 ADRB2
Adrb3-KO S-KO-00948 ADRB3
Htr2c-KO S-KO-02541 HTR2C
Ptpn11-flox S-CKO-04575 SHP2
Stat3-flox S-CKO-05338 STAT3
Stat5a-flox S-CKO-05340 STAT5



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