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Session: Exemplary Trainee Abstracts in Obesity Science Research (Poster Theater Flash Session 8)

(PTFS08-01-24) Liver-Specific Deletion of Cannabinoid 1 Receptor Mitigates Diet-Induced Obesity-Related Hyperinsulinemia and NAFLD in Mice

Sunday, June 30, 2024
2:00 PM – 2:04 PM CT
Location:  W185A-C
YIUNAC

    Presenting Author(s)

  • Gopal Lamichhane, 97829

    Graduate Research Assistant
    Oklahoma State University
    Stillwater, Oklahoma, United States

    Disclosure(s): No relevant financial relationship(s) with ineligible companies to disclose.

    • Co-Author(s)

  • Da-Yeon Lee, MS (she/her/hers)

    PhD Candidate
    Oklahoma State University
    Stillwater, Oklahoma, United States

  • JE

    Josephine M. Egan

    National Institutes of Health (NIH), United States

  • Yoo Kim, PhD

    Assistant Professor
    Oklahoma State University
    Stillwater, Oklahoma, United States

Objectives: This study investigates the effects of hepatic cannabinoid 1 receptor (CB1R) deletion on diet-induced obesity (DIO), focusing on its role in hyperinsulinemia and nonalcoholic fatty liver disease (NAFLD) using the liver-specific CB1R knockout (LCB1KO, hCNR1-/-) mouse model.

Methods: Wild-type (Control, hCNR1+/+) and LCB1KO mice (n=8-12) were subjected to either a high-fat high-sugar diet (HFHSD) or normal chow diet for 15 weeks, with weekly monitoring of body weight and food intake. Evaluation of hepatic and whole-body fat depositions was conducted via 1H NMR and MRI scan. Blood levels of glucose, insulin and related hormones were measured using ELISA assays while pancreas integrity was assessed through immunostaining assays.

Results: HFHSD fed LCB1KO mice showed significantly reduced body weight (43.2±6.4 vs 51.7± 7.7 g, p=0.023) and liver weight (4.8 ±0.7 vs 5.9± 0.3 % w/w body weight, p= 0.012) compared to HFHSD fed control. This reduction in body weight correlated with decreased subcutaneous and epididymal fat mass in LCB1KO mice. 1H NMR analysis revealed a 10-fold lower fat/water ratio in the livers of LCB1KO mice, indicating reduced hepatic fat deposition, supported by lower liver triglyceride (38.4±13.7 vs 152.1±36.0 mg/g, p=0.002) and cholesterol levels (5.4±1.0 vs 7.8±1.2 mg/g, p=0.036), as well as downregulated expression of lipogenesis-related genes (ACC1, PPARγ, FASn, and SREBP1c). These metabolic improvements in LCB1KO mice were associated with amelioration of DIO-induced hyperinsulinemia. LCB1KO mice maintained normal fasting hormone levels, including insulin, amylin, and pancreatic polypeptide YY, regulated downstream signaling transductions. Lower hormone levels were not indicative of pancreatic damage, as evidenced by improved pancreatic islet integrity in LCB1KO mice compared to controls.

Conclusions: Hepatic CB1R plays a crucial role in DIO-induced hyperinsulinemia, exacerbating hepatic fat deposition, and worsening NAFLD. Modulation of hepatic CB1R presents a promising therapeutic strategy to mitigate DIO-induced obesity and NAFLD.

Funding Sources: This research was supported by the Intramural Research Program of the National Institute on Aging and by startup funding from Oklahoma State University.