It’s well established that bariatric surgery is an effective tool to facilitate weight loss and improve medical conditions including diabetes, high blood pressure and high cholesterol. Not as well understood is why it works. Randy Seeley, Ph.D., Henry King Ransom Professor of Surgery, is in constant pursuit of the why.
“My lab focuses on reverse translation: The idea that 70 percent of what we have in medicine are things we know work but we don’t really know why. We have a story we tell to medical students and patients but it doesn’t hold up to a lot of scrutiny. One example of that is bariatric surgery,” Seeley said.
A recent paper published in Cell Metabolism described one more key to understand how the surgery works: The triggering of an increase of an antimicrobial peptide called Regenerating Islet-Derived Protein 3 Gamma (Reg3g), which seems to nod to organ systems to function normally again and is required to maintain weight loss after vertical sleeve gastrectomy (VSG).
When the usual explanation isn’t enough
The most common bariatric surgery procedures, Roux-en-Y (RYGB, commonly referred to as gastric bypass) and VSG, make structural changes to the stomach and small intestine. While the procedures make different structural changes, both result in the portion of the stomach handling food being smaller. This has helped fuel theories that patients lose weight because they feel full more quickly or that the physical changes to the stomach make it malabsorptive, triggering weight loss.
These explanations didn’t satisfy Seeley.
“Patients lose weight after bariatric surgery, but they’re less hungry. If you think of this as wiring your jaw shut but doing it in your gut, you’d be more hungry, and that’s not what happens. So that points to something more complicated in the physiology,” Seeley said.
Looking for a sign
Both high fiber diets and bariatric surgery produce what look like healthier sets of gut bacteria, including the probiotic lactobacillus. Many investigators have looked to the colon to try to ascertain the impacts of this healthier bacteria on the system; the hypothesis is that fecal samples can reveal the effects of metabolites that bacteria triggered to circulate within the body. It’s also relatively simple to get fecal samples to study.
Seeley’s team has focused on the small intestine—where the heavy lifting happens.
“We started focusing more on what happens in the small intestine because the business of the gut happens in the small intestine, all the hard work and all the signals that interact with other parts of your physiology happen there,” Seeley said.
To hunt for candidates in the signaling system between the gut and other organ systems, the team evaluated mice after undertaking three different interventions: Vertical sleeve gastrectomy for some, the introduction of a high-fiber diet for others and the administration of a probiotic to the third group. Their analysis found that all three interventions resulted in a healthier bacterial community in the gut—and that Reg3g, an antimicrobial peptide, was among the most upregulated genes in all cases.
Jay Hoon Shin, a Ph.D. post-doctoral researcher in Seeley’s lab and the first author on the Cell Metabolism paper, thought the peptide demanded a closer look. Seeley wasn’t immediately convinced.
“Everything about it surprised me. Poor Jay Hoon. When he came in with this idea, I didn’t know what Reg3g was. He had to do a lot of convincing to get me interested in this,” Seeley said.
A process of elimination
Shin’s persuasion was effective and the work progressed. The team studied what mice engineered to not produce Reg3g (Reg3g KO mice) looked like after surgical and dietary interventions as well as the pharmacological application of Reg3g compared to wild-type (WT) mice. They then analyzed multiple endpoints to measure the differences in the effects of the interventions on the mice.
The results pointed to a significant role of the gene in regulating energy balance, glucose levels and gut function—and ultimately in the success of bariatric surgery.
Mice fed an unhealthy high-fat diet saw lower expression of Reg3g in multiple segments of the small intestine, but the expression was unchanged in the colon. VSG elevated expression of Reg3g in the small intestine and boosted circulating levels in WT mice, where KO mice didn’t see such changes.
When obese WT and KO mice received VSG surgery, they both experienced initial weight loss, but the WT mice were able to sustain the weight loss 50 days after surgery, while KO mice recovered their body weight at pace with mice that received sham surgery.
The WT mice saw decreased overnight-fasting blood glucose after VSG, an effect absent in the KO mice. WT mice also showed increased glucose tolerance following various administrations of glucose as compared to KO mice, where the effect was largely absent. The administration of Reg3g in conjunction with a glucose test absent surgical intervention was also associated with improved glucose tolerance
It was striking to Seeley just how powerful Reg3g was in facilitating or negating the beneficial effects of the interventions.
“You engineer an animal that doesn’t make Reg3g to find out whether any of the benefits to these manipulations go away and the answer is lots of them go away,” Seeley said.
The team also found that Reg3g modulated the microbiota composition in parts of the small intestine after VSG; KO mice saw different levels of key bacteria in their duodenum than both WT and sham-operated mice after surgery.
They also found that the metabolic effects of a fiber-enriched inulin diet were mediated by Reg3g; mice on that diet saw increased expression of intestinal Reg3g compared to mice on a isocaloric cellulose diet. Unlike WT mice, KO mice didn’t see improved glucose tolerance from such a diet.
One step closer to the “how”
Taken together, these findings suggest that Reg3g is a critical part of bridging the gap from how better bacteria relate to better metabolic regulation—and why bariatric surgery is an effective weight-loss tool for the right patients.
Does the humble peptide hold hope as a therapy for obesity and metabolic conditions like type-2 diabetes?
Seeley thinks it’s possible. In the meantime, he sees a benefit to increased understanding of the mechanisms of the surgery among surgeons and patients.
“If I say I’m cutting away your stomach to make you less hungry, that doesn’t sound great. If I say I'm creating a better environment for your gut to operate the way it’s supposed to, that is consistent with your biology rather than working against it, that’s a message patients can understand and embrace,” Seeley said.