Activation of natriuretic peptides and the sympathetic nervous system following Roux-en-Y gastric bypass is associated with gonadal adipose tissues browning

Abstract

ObjectiveRoux-en-Y gastric bypass (RYGB) is an effective method of weight loss and remediation of type-2 diabetes; however, the mechanisms leading to these improvements are unclear. Additionally, adipocytes within white adipose tissue (WAT) depots can manifest characteristics of brown adipocytes. These ‘BRITE/beige’ adipocytes express uncoupling protein 1 (UCP1) and are associated with improvements in glucose homeostasis and protection from obesity. Interestingly, atrial and B-type natriuretic peptides (NPs) promote BRITE/beige adipocyte enrichment of WAT depots, an effect known as “browning.” Here, we investigate the effect of RYGB surgery on NP, NP receptors, and browning in the gonadal adipose tissues of female mice. We propose that such changes may lead to improvements in metabolic homeostasis commonly observed following RYGB.MethodsWild type, female, C57/Bl6 mice were fed a 60% fat diet ad libitum for six months. Mice were divided into three groups: Sham operated (SO), Roux-en-Y gastric bypass (RYGB), and Weight matched, sham operated (WM-SO). Mice were sacrificed six weeks following surgery and evaluated for differences in body weight, glucose homeostasis, adipocyte morphology, and adipose tissue gene expression.ResultsRYGB and calorie restriction induced similar weight loss and improved glucose metabolism without decreasing food intake. β3-adrenergic receptor expression increased in gonadal adipose tissue, in addition to Nppb (BNP), and NP receptors, Npr1, and Npr2. The ratio of Npr1:Npr3 and Npr2:Npr3 increased in RYGB, but not WM-SO groups. Ucp1 protein and mRNA, as well as additional markers of BRITE/beige adipose tissue and lipolytic genes increased in RYGB mice to a greater extent than calorie-restricted mice.ConclusionsUpregulation of Nppb, Npr1, Npr2, and β3-adrenergic receptors in gonadal adipose tissue following RYGB was associated with increased markers of browning. This browning of gonadal adipose tissue may underpin the positive effect of RYGB on metabolic parameters and may in part be mediated through upregulation of natriuretic peptides.

Caloric Restriction Leads to Browning of White Adipose Tissue through Type 2 Immune Signaling

“…We note that a common feature between the cold exposure and endurance exercise is the negative energy balance: higher energy expenditure than intake leading to fat loss. In addition, interventional microbiota depletion, either by means of antibiotics administration or in germ-free mice (Suá rez-Zamorano et al, 2015;Chevalier et al, 2015), as well as RYGB (Neinast et al, 2015) also increase the browning to a similar extent as several endurance exercise regimens. These are also conditions of decreased caloric uptake and negative energy balance.…”

“…Browning appears consequent to physiological stimuli, such as cold exposure or endurance exercise (Cousin et al, 1992;Guerra et al, 1998;Himms-Hagen et al, 2000). In addition to the physiological stimuli, also microbiota depletion (Suá rez-Zamorano et al, 2015;Chevalier et al, 2015) and Roux-en-Y gastric bypass weight-loss surgery (RYGB) (Neinast et al, 2015) promote the development of beige fat. It remains unclear whether there is a common feature between these seemingly unrelated physiological and interventional stimuli that could lead to the beige fat development.…”

Adipocyte ADRB3 Down-Regulated in Chinese Overweight Individuals Adipocyte ADRB3 in Overweight

“…Furthermore, it was demonstrated that the reduced ADRB3 expression in adipose tissue of obese rats [9, 10] increased after weight loss following Roux-en-Y gastric bypass surgery [25]. Moreover, treatment with ADRB3 agonists caused a noticeable increase of adipose tissue browning and UCP-1 protein level in lean rather than in obese mice [26, 27].…”

Sorting out adipocyte precursors and their role in physiology and disease

“…A great number of pharmacological and physiological stimuli can trigger beige adipocyte accumulation in rodents and humans beyond cold exposure, including cancer cachexia, gastric bypass, exercise, and burn trauma (Kir et al 2014;Neinast et al 2015;Sidossis et al 2015;Stanford et al 2015). Great progress has been made in elucidating the transcriptional machinery and signaling cascades driving brown and beige adipocyte accumulation; however, in most cases, the actual cellular origin of the UCP1 + adipocytes accumulating under physiological conditions or in genetic models has remained unclear.…”