The causal effect of obesity on prediabetes and insulin resistance reveals the important role of adipose tissue in insulin resistance

Abstract

Reverse causality has made it difficult to establish the causal directions between obesity and prediabetes and obesity and insulin resistance. To disentangle whether obesity causally drives prediabetes and insulin resistance already in non-diabetic individuals, we utilized the UK Biobank and METSIM cohort to perform a Mendelian randomization (MR) analyses in the non-diabetic individuals. Our results suggest that both prediabetes and systemic insulin resistance are caused by obesity (p = 1.2×10 −3 and p = 3.1×10 −24). As obesity reflects the amount of body fat, we next studied how adipose tissue affects insulin resistance. We performed both bulk RNA-sequencing and single nucleus RNA sequencing on frozen human subcutaneous adipose biopsies to assess adipose cell-type heterogeneity and mitochondrial (MT) gene expression in insulin resistance. We discovered that the adipose MT gene expression and body fat percent are both independently associated with insulin resistance (p�0.05 for each) when adjusting for the decomposed adipose cell-type proportions. Next, we showed that these 3 factors, adipose MT gene expression, body fat percent, and adipose

Identification of TBX15 as an adipose master trans regulator of abdominal obesity genes

“…Using WGCNA v1.68 [ 39 , 40 ], we confirmed the preservation of the co-expression networks from the METSIM subcutaneous adipose RNA-seq [ 26 ] ( n = 335) in the subcutaneous adipose (v8, n = 581), visceral adipose (v7, n = 277), and skeletal muscle (v8, n = 298) RNA-seq data from the independent GTEx cohort [ 41 , 42 ] and the Mexican MOSS cohort [ 34 ]. We further subdivided the GTEx [ 41 ] cohort to males ( n = 387, n = 149, n = 153, subcutaneous adipose, visceral adipose, skeletal muscle, respectively) and females ( n = 194, n = 84, n = 145, subcutaneous adipose, visceral adipose, skeletal muscle, respectively) and then for the subcutaneous adipose data, lean (BMI < 25, n Males = 102, n Females = 78) and obese (BMI > 30, n Males = 119, n Females = 41) individuals of each sex.…”

“…The participants in the on-going longitudinal Mexican Obesity Study (MOSS) cohort are recruited at the Instituto Nacional de Ciencias Medicas y Nutricion (INCMN), Mexico City, as described in detail in Miao et al [ 34 ]. Briefly, the MOSS cohort consists of Mexican obese individuals undergoing bariatric surgery and participating in a 1-year follow-up.…”

“…Briefly, the MOSS cohort consists of Mexican obese individuals undergoing bariatric surgery and participating in a 1-year follow-up. A total of 43 individuals with subcutaneous adipose RNA-seq data on both time points [ 34 ] were analyzed in our study. The study was approved by the local ethics committee, and all participants gave written informed consent.…”

“…We did not subdivide the visceral and skeletal muscle data into lean and obese categories by BMI as the samples sizes would have been below the recommended minimum threshold for network preservation ( n = 20). The analysis of the MOSS cohort [ 34 ] was also not done in a sex-specific manner due to the small sample size. When sample sizes are above the recommended minimum threshold ( n = 20), the Z Summary score value should not be sensitive to the sample size, and so the relative difference in the number of males and females or lean and obese individuals was not a concern.…”

Study on the Therapeutic Effects of Traditional Chinese Medicine on Insulin Resistance in Obese Mice by Modulating Intestinal Function

“…In addition to upregulating saturated signal hormones to treat obesity, down-regulating food-promoting signals was direction to worth to be thinking, gastrin was the only orexin with peripheral activity, which would enter the brain with blood circulation and enter the hypothalamus through vagus nerve and ucleus of solitary tract (TNS), affecting the center of energy regulation and causing an increase in food intake [10,11]. Increased food intake would lead to obesity, which may lead to insulin resistance in the target tissue [12]. Insulin resistance refers to the pathological state in which insulin promotes glucose uptake and decreased utilization e ciency caused by a variety of reasons, as the main glucose uptake tissue: skeletal muscle and fat play an important role in insulin resistance [13].…”