Research has known for over a decade that an altered microbiota is associated with metabolic syndrome and weight gain. A recent study suggested that bacterial metabolite acetate may drive obesity. Here, we’ll learn why this study shouldn’t be the end of the discussion, and what the literature really says about acetate.

In the last few articles in the short-chain fatty acid (SCFA) series, I discussed the benefits of butyrate, and covered the potential harms of excess butyrate. In this article, I’ll talk about 2-carbon acetate, and its connections with obesity and metabolic syndrome. If you haven’t read my brief overview of SCFAs, be sure to check that out first!

The gut microbiota and obesity

Many studies have now identified links between obesity and the microbiome. In 2006, researchers. showed that genetically obese mice have a microbiome with an increased capacity for harvesting energy from the diet. Moreover, when you transplant fecal material from obese mice into germ-free mice, colonizing them with an “obese microbiome”, the germ-free mice pack on weight and fat.¹

In humans, increased fecal acetate levels are associated with obesity.² But correlation does not necessarily mean causation. A group of researchers at Yale wanted to determine if SCFAs played a causal role in obesity. The study, published in the journal Nature, is titled “Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome”. ² Over the next few sections, I’ll break down their major findings and discuss how it fits in with other acetate research.

Fair warning, this is dense stuff! If you get bogged down in the details, you can always jump to the summary at the end.

Obese rats metabolize more acetate and secrete more insulin

The researchers first discovered that whole-body acetate turnover, blood acetate, and fecal acetate concentrations were significantly increased in rats after 3 days or 4 weeks on an obesity-causing diet. Through several different procedures, they confirmed that the gut microbiota was the source of the elevated acetate.

A simple way to measure the insulin response is to give mice a predetermined amount of glucose and measure the resulting insulin concentrations in the blood. This is called “glucose-stimulated insulin secretion”, or GSIS.  As would be expected, rats fed an obesogenic diet have increased GSIS (they secrete more insulin in response to a glucose stimulus). But rats fed a normal diet AND given acetate infusions into the stomach replicated the increase in GSIS seen in obese rats.

Acetate activates the vagus nerve to drive insulin secretion

The authors next investigated whether acetate could stimulate GSIS through a direct effect on β cells, the cells of the pancreas responsible for insulin secretion. They found that acetate did not stimulate GSIS in isolated pancreatic islets, and other measures of β cell activity were largely unchanged.

They next turned to the parasympathetic nervous system, which regulates β cell insulin secretion.³ This is often called the “rest and digest” nervous system, as it slows the heart rate and increases intestinal activity. The researchers found that parasympathetic activity was increased threefold after 60 min of infusion with acetate. Brain acetate concentrations were also increased, confirming the ability of acetate to cross the blood-brain barrier. Direct infusion of acetate to the brain also caused a massive increase in GSIS.

Stimulation of the vagus nerve has also been shown to drive insulin secretion. The vagus nerve, also called the “great wandering protector”, goes from the brain stem and innervates virtually every abdominal organ, including the gut and pancreas. Was acetate activating the vagus nerve? To find out, they compared the effects of acetate in rats with an intact vagus nerve versus rats in which the vagus nerve was surgically removed. Indeed, vagotomized rats had a significant reduction in plasma insulin concentrations in response to acetate compared to rats with an intact vagus nerve.

The figure below summarizes the findings by Perry et al., showing the gut-brain-β cell axis:

Chronic acetate infusions drive obesity and metabolic syndrome

Finally, the researchers wanted to determine that acetate itself could cause obesity. They gave lean rats continuous acetate infusions into the stomach for 10 days. Rats that received the acetate infusions had increased insulin secretion and insulin resistance. They also had increased parasympathetic nervous system activity, and a threefold increase in plasma grehlin, a hormone that regulates food intake. Acetate-treated rats doubled their daily caloric intake and gained significant weight over the 10 days, despite being fed a normal diet, and had increased plasma, liver, and skeletal muscle triglyceride content. Rats with vagotomy did not have these effects, again demonstrating that the effects of acetate were mediated through the vagus nerve.

So gut-derived acetate causes obesity, right? Not so fast.

From this comprehensive study in such a prestigious journal, you’d think there should be no question that elevated gut acetate causes obesity, right? Yet the findings from this study are in stark contrast with in vitro studies and multiple animal studies that show benefits of acetate on metabolism. Let’s look at a few.

In vitro studies:

Kimura et al. Acetate binds to the receptor GPR43 in several target organs. In cultured gut epithelial cells, it results in the secretion of a gut-derived hormone that regulates energy metabolism. In adipose tissue, GPR43 activation inhibits insulin signaling and suppresses fat accumulation. Systemically, this improves insulin sensitivity.⁴

Animal studies:

Kimura et al. found that mice that are deficient in the acetate receptor GPR43 become obese when fed a normal diet, whereas mice who overexpress GPR43 remain lean even when fed an obesogenic diet.⁴

Sahuri et al. gave nanoparticle-delivered acetate to diet-induced obese mice. In the liver, acetate reduced lipid accumulation, improved liver function, and increased mitochondrial efficiency. In white adipose tissue, acetate inhibited fat breakdown but induced ‘browning’, increasing the metabolic capacity and leading to a reduction in body fat.⁵

Frost et al. showed that prebiotics such as inulin increased acetate production that crosses the blood-brain barrier of rats and results in reduced grehlin production. This leads to a reduction of food intake, body weight, and fat mass.⁶

Everard et al. found that prebiotic fructooligosaccharides increase acetate production, and that this is associated with reduced body weight and fat mass, decreased diabetes, and a lower food intake in mice.⁷

Li & Xie et al. showed that in diet-induced obese mice, every-other day fasting (EODF) elevated serum acetate and lactate levels, which was associated with the browning of white adipose tissue and metabolic improvements.⁸

Acetate has been shown to have other benefits as well:

• Increases IgA, which protects the gut barrier⁹
• Protects against neuroinflammation from LPS, an endotoxin from the gut bacteria¹⁰
• Improves recovery from traumatic brain injury and reduces proliferation of cancerous glioblastoma stem cells.^11,12
• Is the primary fuel for brain cells called astrocytes and may be responsible for the beneficial anti-epileptic effects of ketosis.¹³ During ketosis, the brain imports huge amounts of acetate. Astrocytes convert acetate to glutamine,^14,15 which is a precursor to the inhibitory neurotransmitter GABA.¹⁶

What was most disappointing to me is that despite being published in the same prestigious journal (Nature) as many of the studies it contradicts, the discussion section of the study by Perry et al. made no mention of previous acetate literature. Even a summary of the study, written by prominent microbiome researcher Martin Blaser, made no mention of previous acetate research.¹⁷

So what gives? What could explain these discrepant findings?

Since they failed to explain these obvious discrepancies, I’ll offer a few possible explanations:

1) Model: Perry et al. used rats in their study, while most other studies on acetate and obesity or metabolic syndrome have used one of several strains of mice. Still, rats and mice are similar in their physiology, so it’s unlikely that this explains all of the differences.

2) Mode of delivery: there is likely a difference between intragastric (into the stomach) and oral or colonic acetate. As Canfora et al. point out,

“Continuous intragastrically supplied acetate might influence the pH of the stomach and thereby might influence gastric emptying and food release, digestion and absorption, and hormonal regulation.” ¹⁸

Additionally, the expression of receptors for acetate are not uniform throughout the GI tract. Later, I’ll discuss some human studies that found differential effects depending on acetate location.

2) Dosage: As we saw with butyrate, the dosage of SCFAs is incredibly important. It’s unlikely that the large dosage of acetate used by Perry et al. reflects anything that could be normally produced by the gut microbiota or consumed in the diet.

3) SCFA ratios: Colonic bacteria can transform acetate into other SCFAs. In most healthy people, SCFAs are present in a 3:1:1 ratio.¹⁹ It’s possible that skewing this ratio by providing acetate alone is not physiologically relevant, and results in different metabolic effects.

So, can supraphysiologic doses of intragastric acetate cause metabolic syndrome? Yes. Perry et al. show that quite elegantly. But does gut microbiota-derived acetate drive metabolic syndrome? Probably not.

Is there anything we take away from the study by Perry et al.? Yes. First, acetate turnover is influenced by the gut and elevated in obesity. Secondly, acetate probably does activate the vagus nerve to cause insulin secretion, as injecting acetate into the brain corroborated the findings from intragastric infusion. So these two things are likely true….at least in animals!

The real kicker: human and animal receptors respond differently to acetate

WHAT?!? If this article feels like a bit of a roller coaster, trust me, it was even more of a roller coaster to wade through all this literature and try to distill it into a single article. I thought I had a good understanding of acetate before I started writing this, but boy was I wrong. I even wrote two other versions of this article, only to have to start from square one when I found more contradictory literature hidden in a few smaller journals that didn’t receive the attention they deserved.

Anyways, at least three studies show that GPR43, the primary receptor for acetate, responds differently to stimulation in both mice and humans:

Priyadarshini et al. showed that in mouse islets, signaling via GPR43 can either enhance or inhibit GSIS, depending on the signaling pathways activated. In human islets, acetate stimulation of GPR43 did not affect GSIS.²⁰

Ang et al. showed that stimulating GPR43 on mouse immune cells with acetate resulted in the release of proinflammatory cytokines. In human immune cells, acetate attenuated the release of proinflammatory cytokines.²¹

Dewulf et al. showed that contrary to findings in mice,²² acetate stimulation of GPR43 did not induce differentiation of human adipocytes.²³

This is just one of many cases where animal models fall short. It is unfortunately quite common in nutritional sciences research, and especially in cases of fatty acid metabolism. Mice simply don’t metabolize fat the same way that humans do.

Human studies with acetate and metabolism

Alright, so we can’t rely on animal models to tell us about the effects of acetate on metabolism in humans. Luckily, there are a fair number of human studies looking at acetate.

Canfora et al. gave colonic infusions of SCFA mixtures to overweight and obese men and found that it increased fat oxidation, energy expenditure, and the satiety peptide PYY, while inhibiting lipolysis (fat breakdown).²⁴ The last one may seem like a negative role of acetate, but data from overweight humans suggest that a partial inhibition of lipolysis within cells actually prevents fat accumulation and insulin resistance, without affecting fat mass in the long term.²⁵

Van der beek et al. gave colonic infusions of acetate either to the distal colon (closer to the rectum) or proximal colon (closer to the small intestine). Distal acetate increased fasting fat metabolism and fasting peptide YY and reduced a marker of gut inflammation, while proximal acetate had no effects.²⁶

Liljeberg et al. studied the effects of vinegar, which contains between 4 and 8% acetate,^27,28 on postprandial glucose (PPG) and insulin (PPI) levels. Vinegar consumption reduced gastric emptying rate by 20% and decreased both PPG and PPI.²⁵

Overall, the human literature seems to suggest benefits of distal acetate on metabolism, though the evidence is limited and inconclusive. Further research is needed to definitively elucidate the role of acetate in humans.

Putting it all together

Like all SCFAs, acetate appears to play nuanced roles in host physiology, and we don’t yet understand them completely. Let’s review what we’ve covered:

• Animal studies on acetate and metabolic syndrome have mixed results, likely due to differences in mode of delivery, dosage, and SCFA ratios.
• Acetate has benefits for the brain and immune system
• Humans and animals respond to acetate differently, so we can’t rely on animal studies to tell us about acetate’s role in humans.
• Limited human studies seem to suggest that acetate has beneficial effects on metabolism
• The location of acetate seems to matter. Acetate produced in more distal parts of the colon seems to have the most beneficial effects.

That’s all for now! Be sure to stay tuned for part 5, where I’ll be discussing the propionate-autism connection. Subscribe at the bottom of the page and never miss a post!

Sources:

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