Nobiletin, a Citrus Molecule, Reverses Insulin Resistance and Blood Fats: Mystery as to Why Remains

nobiletin

Researchers at Western University are studying a molecule found in sweet oranges and tangerines called nobiletin, which they have shown to drastically reduce obesity and reverse its negative side-effects.

But why it works remains a mystery.

Research published in the Journal of Lipid Research demonstrates that mice fed a high-fat, high-cholesterol diet that were also given nobiletin were noticeably leaner and had reduced levels of insulin resistance and blood fats compared to mice that were fed a high-fat, high-cholesterol diet alone.

“We went on to show that we can also intervene with nobiletin,” said Murray Huff, PhD, a Professor at Western’s Schulich School of Medicine & Dentistry who has been studying nobiletin’s effects for over a decade. “We’ve shown that in mice that already have all the negative symptoms of obesity, we can use nobelitin to reverse those symptoms, and even start to regress plaque build-up in the arteries, known as atherosclerosis.”

But Huff says he and his team at Robarts Research Institute at Western still haven’t been able to pinpoint exactly how nobiletin works. The researchers hypothesized that the molecule was likely acting on the AMP Kinase pathway, which turns on the machinery in the body that burns fats to create energy, and it also blocks the manufacture of fats.

However, when the researchers studied nobiletin’s effects on mice that had been genetically modified to remove AMP Kinase, the effects were the same.

“This result told us that nobiletin is not acting on AMP Kinase, and is bypassing this major regulator of how fat is used in the body,” said Huff. “What it still leaves us with is the question – how is nobiletin doing this?”

  • Nobiletin increased phosphorylation of AMPK and ACC in primary mouse hepatocytes, which was associated with increased FA oxidation and attenuated FA synthesis.
  • Despite loss of ACC phosphorylation in Ampkβ1−/− hepatocytes, nobiletin suppressed FA synthesis and enhanced FA oxidation. Acute injection of nobiletin into mice did not increase phosphorylation of either AMPK or ACC in liver.
  • In mice fed a high-fat diet, nobiletin robustly prevented obesity, hepatic steatosis, dyslipidemia, and insulin resistance, and it improved energy expenditure in Ampkβ1−/−, AccDKI, and iβ1β2AKO mice to the same extent as in WT controls.
  • Thus, the beneficial metabolic effects of nobiletin in vivo are conferred independently of hepatic or adipocyte AMPK activation.

Huff says while the mystery remains, this result is still clinically important because it shows that nobiletin won’t interfere with other drugs that act on the AMP Kinase system. He says current therapeutics for diabetes like metformin for example, work through this pathway.

“Obesity and its resulting metabolic syndromes are a huge burden to our health care system, and we have very few interventions that have been shown to work effectively,” said Huff. “We need to continue this emphasis on the discovery of new therapeutics.”

The next step is to move these studies into humans to determine if nobiletin has the same positive metabolic effects in human trials.

Source: Nadya M Morrow et al, The citrus flavonoid nobiletin confers protection from metabolic dysregulation in high-fat-fed mice independent of AMPK. The Journal of Lipid Research. 2020; 61, 387-402.