Loss of Uncoupling Protein 3 Attenuates Western Diet–Induced Obesity, Systemic Inflammation, and Insulin Resistance in Rats

Abstract

Objective Uncoupling protein 3 (UCP3) is a mitochondrial carrier related to fatty acid metabolism. Although gene variants of UCP3 are associated with human obesity, their contribution to increased adiposity remains unclear. This study investigated the impact that loss of UCP3 has on diet‐induced obesity in rats. Methods Male UCP3 knockout rats (ucp3−/−) and wild‐type littermates (ucp3+/+) were fed a high‐fat, high‐carbohydrate Western diet for 21 weeks. Body composition was analyzed by EchoMRI. Whole‐body insulin sensitivity and rates of tissue glucose uptake were determined by using hyperinsulinemic‐euglycemic clamp. Changes in tissue physiology were interrogated by microscopy and RNA sequencing. Results Loss of UCP3 decreased fat mass gain, white adipocytes size, and systemic inflammation. The ucp3−/− rats also exhibited preserved insulin sensitivity and increased glucose uptake in interscapular brown adipose tissue (iBAT). Brown adipocytes from ucp3−/− rats were protected from cellular degeneration caused by lipid accumulation and from reactive oxygen species–induced protein sulfonation. Increased glutathione levels in iBAT from ucp3−/− rats were linked to upregulation of genes encoding enzymes from the transsulfuration pathway in that tissue. Conclusions Loss of UCP3 partially protects rats from diet‐induced obesity. This phenotype is related to induction of a compensatory antioxidant mechanism and prevention of iBAT whitening.

Natural Extracts to Augment Energy Expenditure as a Complementary Approach to Tackle Obesity and Associated Metabolic Alterations

“…To evaluate the potential of the extracts in the activation of thermogenesis and mitochondrial oxidative capacity, first, we analyzed their effects in the modulation of the expression of the following genes: uncoupling proteins ( UCP1, UCP2, UCP3 ) which are key players in the activation of mitochondrial thermogenesis [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ]; PR domain containing 16 ( PRDM16 ) and Bone morphogenetic protein 8B ( BMP8B ) [ 53 , 54 ] as browning activators; PPARG as the adipocyte differentiation inductor [ 55 , 56 ]; genes related to mitochondrial function and biogenesis, such as Peroxisome proliferator-activated receptor gamma coactivator 1-alpha ( PGC1A ) [ 57 , 58 ], Sirtuin 1 ( SIRT1 ) [ 47 , 59 , 60 , 61 ], Mitochondrial Transcription Factor 1 ( TFAM1 ) [ 62 , 63 ], 5’ adenosine monophosphate-activated protein kinase ( AMPK ) [ 30 , 64 , 65 , 66 ], and Mitochondrial creatine kinase ( CKMT ) [ 67 , 68 ]; genes implicated in glucose uptake and insulin homeostasis, such as Glucose transporter type 4 ( SLC2A4/GLUT4 ) [ 69 ] and Insulin receptor substrate 1 ( IRS1 ) [ 70 , 71 ]; genes related to lipid homeostasis [ 72 ] such as Sterol regulatory element-binding transcription factor 1 ( SREBF1 ) [ 73 , 74 ], Fatty acid synthase ( FASN ) [ 75 , 76 ...…”

UCP3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin II‐Induced Hypertension

“…Generation of the Sprague Dawley rat model of UCP3 haploinsufficiency has been reported previously. 10 Because lack of UCP3 has no impact on adiposity or insulin sensitivity in rats maintained under conventional housing conditions, 17 the model allowed testing of the present hypothesis independently from the confounding effects of obesity and diabetes. Male UCP3 insufficient rats (ucp3 +/‐ ) and wild‐type controls (ucp3 +/+ ) were obtained from same litters by non‐brother‐sister mating of heterozygous knockout rats.…”

Metabolic basis of solute carrier transporters in treatment of type 2 diabetes mellitus

“…The role of UCP3 remains controversial in the literature. Loss of UCP3 function in muscle has been reported to enhance glucose uptake, improve glucose tolerance, and increase insulin sensitivity in diet-induced obese (DIO) rats 81 . Conversely, overexpression of UCP3 in muscle has also been shown to improve insulin sensitivity in HFD-induced obese mice 82 .…”