Use of dietary and pharmaceutical therapies to reduce weight and improve metabolism of a diet-induced obese (DIO) mouse model

Kang, Yifei

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https://hdl.handle.net/2142/120508 Copy

Description

Title

Use of dietary and pharmaceutical therapies to reduce weight and improve metabolism of a diet-induced obese (DIO) mouse model

Author(s)

Kang, Yifei

Issue Date

2023-04-12

Director of Research (if dissertation) or Advisor (if thesis)

Swanson, Kelly S

Doctoral Committee Chair(s)

Holscher, Hannah D

Committee Member(s)

• Nelson, Erik R
• Pan, Yuan-Xiang

Department of Study

Nutritional Sciences

Discipline

Nutritional Sciences

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Obesity
• Metabolism
• Microbiota

Language

eng

Abstract

Obesity is a major public health concern, as it increases the risk of developing chronic diseases such as type 2 diabetes, heart disease, stroke, and some cancers. The treatment of obesity is multifaceted and involves lifestyle modifications, pharmacotherapy, and surgery. Lifestyle interventions such as dietary changes, increased physical activity, and behavioral therapy are the first-line treatment for obesity, and can result in significant weight loss and improvements in metabolic health. Pharmacotherapy involves the use of medications to suppress appetite, reduce food intake, or block fat absorption, and can be effective for some patients. In addition, the alterations in the composition and function of the gut microbiota may contribute to the development of obesity, insulin resistance, and metabolic disorders. The aims of this dissertation were to evaluate the effects of a dextran-conjugated saroglitazar (Dex-Saro) nanomedicine, and mealworm-based dietary interventions on the physiological outcomes and gut microbiota populations of diet-induced obesity mice. In all studies, male C57BL/6J mice were fed a high-fat diet (HFD) to induce obesity and metabolic syndrome, with a low-fat diet (LFD) group of mice serving as lean controls. After metabolic syndrome was confirmed by glucose tolerance testing, mice were allotted to treatment groups. Two nanomedicine studies were conducted. In the first study, obese mice were given a single dose of saline (injection), free saroglitazar (5.0 mg/kg BW injection or oral administration), or Dex-Saro (0.1, 0.7, or 5.0 mg/kg BW injection). Lean mice also received a saline injection. Acute effects on circulating liver enzymes and triglycerides and tissue histology and gene expression analysis were measured. The Dex-Saro nanomedicine had minor effects on tissue gene expression and showed no adverse effects in the acute study, indicating safety for long-term treatment. Given the lack of adverse effects measured in the acute study, it was followed by a 4-week study. Obese mice were given injections of saline, dextran, free saroglitazar (5.0 mg/kg BW), or Dex-Saro (0.7 mg/kg BW) every 2 days. Lean controls received saline injections every 2 days. Glucose tolerance testing was performed every 2 weeks. At sacrifice, blood samples were collected for liver enzymes and triglycerides. Liver tissue was collected to measure weight, triglycerides, histology, and gene expression. Adipose tissue was collected to measure weight, histology and gene expression. Cecal digesta samples were collected for microbiota analysis. Long-term treatment of Dex-Saro led to substantial weight loss compared with obese controls. This was accompanied by improvements in glucose tolerance, lower adipose tissue weight, and improved hepatic steatosis scores, as well as changes in the expression of genes associated with energy balance, glucose metabolism, and lipid metabolism. In addition, Dex-Saro led to beneficial alterations to the cecal microbiota populations, including a lower Firmicutes:Bacteroidetes ratio and higher abundance of the butyrate producing bacteria Roseburia. Correlation analysis revealed negative correlations between beneficial bacterial genera, including Dubosiella, Bifidobacterium, Anaeroplasma, and Faecalibaculum, with adipose tissue weight. In the mealworm study, mice were fed HFD containing yellow mealworm (Tenebrio molitor)- or lesser mealworm (Alphitobius diaperinus)-based proteins to partially (50%) or completely (100%) replace casein as the protein source. Food intake was recorded every 2 days, BW, body composition, and glucose tolerance testing were measured every 2 weeks, and fecal samples were collected every 2 weeks. After 8 weeks, animals were euthanized. Serum was collected for liver enzymes and lipid profiles, perirenal adipose tissue and liver tissue samples were collected for gene expression, histopathology, and triglyceride analysis, and cecal digesta samples were collected for microbiota analysis. Mealworm-based proteins led to lower weight gain rate and improved blood lipid metabolites, including lower cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol, higher high-density lipoprotein (HDL) cholesterol, and lower LDL/HDL ratio. Mealworm-based diets also altered glucose and lipid metabolism genes in the liver, and to a lesser extent, in adipose tissue. In addition, the microbiota of mealworm-fed mice were altered compared with obese controls. In fecal samples, mice fed mealworm diets had greater bacterial alpha diversity, with alpha diversity changes occurring in a time-dependent manner. Beta diversity analyses of fecal samples showed a clear separation of treatments in a time-dependent manner, with mice fed mealworm-based diets clustering separately from obese controls. In cecal digesta, alpha diversity indexes were greater in all groups of mice fed mealworm-based diets than obese controls. Beta diversity analysis showed clear separation between mice fed mealworm-based diets and obese controls. Correlation analysis identified significant relationships between 27 bacterial genera and blood lipid metabolite concentrations, with most being related with HDL cholesterol. In conclusion, the Dex-Saro nanomedicine was found to be promising in reducing weight, improving metabolism, and beneficially shifting gut microbiota in diet-induced obesity mice. The novel dietary treatments of mealworm-based proteins were found to regulate weight gain rate, improve blood lipid metabolites, and had profound changes to the gut microbiota populations in diet-induced obesity mice.

Graduation Semester

2023-05

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/120508

Copyright and License Information

Copyright 2023 Yifei Kang

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