Those who must hit the low-carb, high-fat diets to trim the bulging waistline may take heart. Finally, science has proof to show how such slimming diets, such as Atkins’s formula, work — at least in mice and monkeys.
Mammals’ ability to switch to “fuel” from fat stores when the level of glucose — the body’s primary energy source — plummets depends on a key “starvation hormone” released by the liver. Early this month, scientists unravelled the mechanism behind this liver hormone, which belongs to a super family of hormones called Fibroblast Growth Factor (FGF). The hormone, called FGF-21, in mice (its equivalent in humans is FGF-15) gets activated when normal, carbohydrate-rich food is denied for more than 24 hours. Prolonged fasting, too, triggers a similar mechanism.
Scientists have known for a while that during periods of nutrient deprivation, mammals turn to fat tissues for meeting their energy requirement. It is said that during prolonged fasts, “ketone bodies” (produced from fatty acids transferred from storage in fat tissues to the liver when carbohydrates are scarce) can provide nearly half the baseline energy requirement and up to 70 per cent of the energy needed by the brain. Earlier studies have also shown that feeding rodents with a high-fat, low-carbohydrate (“ketogenic”) diet induces fat oxidation with associated weight loss. But what triggers this switch and its exact underlying metabolic mechanism was by and large unknown.
The mystery was finally solved when two independent teams of researchers got to the bottom of how FGF-21 works in mice. While a team of researchers led by Eleftheria Maratos-Flier of Harvard University discovered how FGF-21 plays a key role in the metabolic shift when the animals are fed with low-carbohydrate, high-fat food, another group led by Steven Kliewer of University of Texas Southwestern Medical Center found that the liver hormone helps mice to survive starvation by getting them into a hibernation-like state, known as torpor, which helps to conserve energy. Their studies appeared recently in the journal, Cell Metabolism.
Maratos-Flier and her colleagues found that when a diet low in starches and sugars was fed to mice, there was a nearly 25-fold increase in FGF-21 levels after about 24 hours. But when the normal diet was restored, there was a drastic drop in the hormone levels, clearly pointing to FGF-21’s role. “We saw a dramatic increase in FGF-21 in the livers of mice on the diet,” she said, adding, “We thought maybe there is something to this.”
The Harvard University team found that mice put on a low-carbohydrate, high-fat diet for 30 days lost weight substantially. Significantly, the rodents maintained normal levels of circulating lipids such as “good” cholesterol and blood glucose.
The scientists believe that better understanding of this metabolic pathway can not only lead to ways to efficiently fight obesity, but also provide a new line of treatment for managing several metabolic disorders such as diabetes.
“What is really exciting is that mice with excess FGF-21 — even when they are fed — look like they are fasted,” Kliewer said. “It’s startling that you can flip the whole metabolic profile by just inducing one hormone.”
Kliewer’s group showed that FGF-21 is induced directly by a biomolecule called peroxisome proliferator-activated receptor-alpha (PPAR-alpha). PPAR-alpha is known to control the use of fat as an energy source during starvation. FGF-21, in turn, stimulates lipid breakdown in white adipose tissue and ketone body production in the liver. They unexpectedly also observed that FGF-21 led animals to reduce their physical activity and made them more sensitive to entering torpor.
“When you step back, this whole thing makes sense,” said Kliewer. “During fasting, the liver hormone communicates to the adipose tissue to send fat to the liver. It turns on the metabolism of fat into ketone bodies. And at the same time, it sensitises the animals to go into torpor to conserve energy. It’s clear that FGF-21 is a principal component of the fasting and starvation response.”
The two studies clearly indicate that FGF-21 is responsible for the proposed positive effect of the Atkins diet — including weight loss and increase in good cholesterol. “It is possible that FGF-21 or drugs that activate this molecular pathway could be used to treat obesity in humans. But this remains to be determined,” Kliewer told KnowHow.
However, the credit for recognising the hormone’s potential to regulate metabolism goes to a team of researchers from the US-based pharmaceutical company, Eli Lilly. In February, the Eli Lilly team led by Alexei Kharitonenkov demonstrated that transgenic mice that overexpressed FGF-21 were protected from diet-induced obesity, had smaller fat cells and had more brown adipose tissue. Brown fat helps regulate body temperature, unlike white adipose tissues that are merely fat deposits. The study, that appeared in the journal Endocrinology, reported that administration of FGF-21 reduced blood sugar levels and triglycerides to near-normal levels in rodents that were rendered diabetic through genetic manipulation. “Importantly, these effects were durable and did not come at the expense of weight gain or hypoglycaemia,” Kharitonenkov said.
Currently, Kharitonenkov’s team is trying to develop drugs that exploit the positive traits of the FGF-21 hormone.