The effects of sodium butyrate supplementation on the expression levels of PGC-1α, PPARα, and UCP-1 genes, serum level of GLP-1, metabolic parameters, and anthropometric indices in obese individuals on weight loss diet: a study protocol for a triple-blind, randomized, placebo-controlled clinical trial

Trials (2023) 24:489 Amiri et al. Trials https://doi.org/10.1186/s13063-022-06891-9 Open Access STUDY PROTOCOL The effects of sodium butyrate supplementation on the expression levels of PGC‑1α, PPARα, and UCP‑1 genes, serum level of GLP‑1, metabolic parameters, and anthropometric indices in obese individuals on weight loss diet: a study protocol for a triple‑blind, randomized, placebo‑controlled clinical trial Parichehr Amiri1,2*, Seyed Ahmad Hosseini2,3*, Neda Roshanravan4, Maryam Saghafi‑Asl5 and Mitra Tootoonchian6 Abstract Background Obesity is a multifaceted disease characterized by an abnormal accumulation of adipose tissue. Grow‑ ing evidence has proposed microbiota-derived metabolites as a potential factor in the pathophysiology of obesity and related metabolic conditions over the last decade. As one of the essential metabolites, butyrate affects sev‑ eral host cellular mechanisms related to appetite sensations and weight control. However, the effects of butyrate on obesity in humans have yet to be studied. Thus, the present study was aimed to evaluate the effects of sodium butyrate (SB) supplementation on the expression levels of peroxisome proliferator activated-receptor (PPAR) gamma coactivator-1α (PGC-1α), PPARα and uncoupling protein 1 (UCP1) genes, serum level of glucagon-like peptide (GLP1), and metabolic parameters, as well as anthropometric indices in obese individuals on a weight loss diet. Methods This triple-blind randomized controlled trial (RCT) will include 50 eligible obese subjects aged between 18 and 60 years. Participants will be randomly assigned into two groups: 8 weeks of SB (600 mg/day) + hypo-caloric diet or placebo (600 mg/day) + hypo-caloric diet. At weeks 0 and 8, distinct objectives will be pursued: (1) PGC-1α, PPARα, and UCP1 genes expression will be evaluated by real-time polymerase chain reaction; (2) biochemical parameters will be assayed using enzymatic methods; and (3) insulin and GLP1 serum level will be assessed by enzyme-linked immunosorbent assay kit. *Correspondence: Parichehr Amiri Seyed Ahmad Hosseini Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Amiri et al. Trials (2023) 24:489 Page 2 of 8 Discussion New evidence from this trial may help fill the knowledge gap in this realm and facilitate multi-center clinical trials with a substantially larger sample size. Trial registration Iranian Registry of Clinical Trials: IRCT20190303042905N2. Registered on 31 January 2021. Keywords Sodium butyrate, Obesity, Energy metabolism genes, Appetite, Randomized controlled trial Introduction Obesity is caused by a positive energy imbalance when energy consumed exceeds energy expenditure [1]. Obesity plays a crucial role in the genesis of many chronic disorders, including cardiovascular disease, type 2 diabetes mellitus (T2DM), rheumatoid arthritis, and various cancers, causing complications such as glucose intolerance, insulin resistance (IR), systemic inflammation, hyperlipidemia, and hypertension [2, 3]. The World Health Organization (WHO) estimates that the global prevalence of obesity has tripled since 1975 [4]. If current trends continue, by 2025, there will be 2.7 billion overweight people and more than 1 billion obese people [4]. This demonstrates that obesity has steadily increased over the last few decades and is now a global health concern [1]. Obesity is a multifactorial disease in which, in addition to heredity, environmental, social, physiological, and metabolic factors all play an essential role in its occurrence [5]. The appetite of obese people usually increases, while their energy expenditure decreases, owing to insufficient physical activity and brown adipose tissue (BAT) dysfunction [6]. BAT contributes significantly to energy expenditure by burning triglycerides (TG) and glucose in humans [7]. In recent years, researches on the relation of intestinal microbiota with obesity and epigenetic modifications have remarkably grown. The metabolic functions of the intestinal microbiota are the fermentation of dietary fiber and the production of short-chain fatty acids (SCFAs) [8]. In the lumen of the colon, the significant SCFAs are acetate (C2), propionate (C3), and butyrate (C4) in a 1:1:3 molar ratios. Increased bacterial fermentation of SCFAs contributes to the regulation of systemic energy by reducing hepatic production of glucose and lipids [9, 10]. Animal models of metabolic diseases have reported that among all SCFAs, butyrate has the highest anti-obesity activity [11]. There are several mechanisms through which butyrate works, including preventing weight gain caused by a high-fat diet (HFD), reducing serum TG, total cholesterol, glucose, IR, and improving hepatic steatosis [11, 12]. Firmicutes and Bacteroides are the two main types of butyrate-producing bacteria; previous research has shown that these bacteria are reduced in the obese people [13]. On the other hand, a study showed that the butyrate-producing bacteria are higher in lean people, and when these bacteria are transferred to the intestines of people with metabolic syndrome (MetS), their IR status improves [14]. Treatment of obesity and obesity-related disturbances depends mainly on diet, exercise, and drugs to treat specific components, such as orlistat, metformin, and statins [15, 16]. This pharmaceutical strategy can lead to drug interactions, as people with MetS may require several medications [17]. Additionally, treating one component of MetS can harm another [15]. In this regard, butyrate, a microbial metabolite, has recently sparked much interest as a safe supplement that could decrease weight, serum glucose, cholesterol, and blood pressure while having minimal side effects [11, 12, 18]. Butyrate, a histone deacetylase inhibitor, could hyper-acetylate transcription factors and change several genes expression level especially peroxisome proliferator (...truncated)