ABSTRACT
Objective Intestinal gluconeogenesis, via the initiation of a gut-brain nervous circuit, accounts for the metabolic benefits linked to dietary proteins or fermentable fibre in rodents and has been positively correlated with the rapid amelioration of body weight after gastric bypass surgery in obese humans. In particular, the activation of intestinal gluconeogenesis moderates the development of hepatic steatosis accompanying obesity. In this study, we investigated the specific effects of intestinal gluconeogenesis on adipose tissue metabolism, independently of its induction by nutritional manipulation.
Methods We used two transgenic mouse models of suppression or overexpression of G6PC, the catalytic subunit of glucose-6 phosphatase, the key enzyme of endogenous glucose production, specifically in the intestine.
Results Under a hypercaloric diet, mice with a genetic overexpression of intestinal gluconeogenesis showed a lower adiposity and higher thermogenic capacities than wild-type mice, featuring marked browning of white adipose tissue and prevention of the whitening of brown adipose tissue. Suppression of sympathetic nervous signalling in brown adipose tissue impairs the activation of thermogenesis. Conversely, mice with genetic suppression of intestinal gluconeogenesis exhibit an increase in adiposity under standard diet, associated with a decreased expression of markers of thermogenesis in both the brown and white adipose tissues.
Conclusion Intestinal gluconeogenesis is sufficient in itself to activate the sympathetic nervous system and prevent the expansion and the metabolic alterations of brown and white adipose tissues metabolism under high calorie diet, thus preventing the development of obesity. These data increase knowledge of the mechanisms of weight reduction in gastric bypass surgery and pave the way of new approaches to prevent or cure obesity.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Lead contact: Gilles Mithieux (gilles.mithieux{at}inserm.fr), Tel: + 33 478 77 87 88
ABBREVIATIONS
- AdipoQ
- Adiponectin gene
- ADP
- Adenosine diphosphate
- Adrβ3
- β3-adrenergic receptor
- BAT
- Brown adipose tissue
- CoxIV
- Cytochrome c oxidase subunit 4
- eWAT
- Epididymal white adipose tissue
- FADH2
- Dihydroflavine-adenine dinucleotide
- FCCP
- p-trifluoromethoxy-carbonyl-cyanide-phenyl hydrazone
- G6Pase
- Glucose-6-phosphatase
- G6PC
- Catalytic subunit of Glucose-6-phosphatase
- HF-HS
- Hgh fat-high sucrose
- HMW
- high molecular weight form of adiponectin
- Hsl
- Hormone sensitive lipase
- IGN
- Intestinal gluconeogenesis
- MRI
- Magnetic resonance imaging
- 6-OHDA
- 6-hydroxydopamine
- Ppara
- Peroxisome proliferator-activated receptor α
- Ppargc1a
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-α
- PRDM16
- PR domain containing 16
- PVDF
- Polyvinylidene fluoride
- scWAT
- Subcutaneous white adipose tissue
- SDS
- Sodium dodecyl sulfate
- SEM
- Standard error of the mean
- SGLT3
- Sodium-glucose co-transporter 3
- SNS
- Sympathetic nervous system
- TH
- Tyrosine hydroxylase
- TNFα
- Tumor necrosis factor α
- UCP1
- Uncoupling Protein 1
- WAT
- White adipose tissue
- WT
- Wild-type