A protein known as ATPase inhibitory factor I (IF1) was seen to limit obesity in mice on a high-fat diet by regulating genetic activity related to appetite in a sex-specific manner, researchers report.
Using data from a large-scale study, the team from South Korea also found that a variant in the gene coding for IF1 was associated with lesser obesity in men but not in women.
The study, “Sex specific effect of ATPase inhibitory factor 1 on body weight: studies in high fat diet induced obese mice and genetic association studies in humans,“was published in the journal Metabolism.
IF1 is a protein that suppresses the breakdown of ATP, a small molecule used as “fuel” by all cells in the body.
Previous work by some of the same investigators had discovered that IF1 exerts an anti-diabetic effect in men by regulating sugar metabolism through the production of ATP. As men have been shown to lose weight through exercise while women do not, the researchers set out to find if IF1 activity might be linked to this inequality in the benefits of exercise across the sexes.
They fed mice a high-fat diet for six weeks to induce obesity. They then gave a subset of those mice IF1 (5 mg/kg, via injection into the abdomen) and analyzed its effects on body weight.
Results showed that IF1 treatment prevented weight gain in male mice. This was associated with lesser food consumption in IF1-treated mice than in untreated mice. In fact, mice given IF1 ate an amount of food similar to a control group fed a normal fat diet and not treated with IF1.
Animals given IF1 had less visceral fat, including less subcutaneous (under the skin) fat, smaller fat cells, and greater muscle weight in the hind paws than did untreated mice on high-fat diet.
Mice given IF1 also showed similar blood levels of leptin, a hormone that suppresses hunger, to those seen in controls, as well as improved glucose (sugar) metabolism.
Experiments in cells from the hypothalamus, a brain area that plays a crucial role in hunger control, showed that IF1 activated genetic pathways known to decrease hunger by inducing satiety (feeling full).
The researchers then used two sets of female mice, also on a high fat diet, to evaluate the sex-specific effects of IF1 treatment. Mice in one of these groups had their ovaries removed (OVX mice) to eliminate the effects of ovarian hormones, mainly estrogen and progesterone.
While younger mice (5 weeks old) had no significant weight changes and only modest decreases in food intake and visceral fat in response to IF1 treatment, OVX mice (8 weeks old) experienced significant declines in body weight, food intake, and visceral fat. These animals also showed biochemical changes similar to IF1-treated males. This suggests that ovarian hormones influence the observed sex differences.
Finally, the researchers looked for associations between genetic variants of the IF1 gene and obesity using the Korean Genome and Epidemiology Study (KoGES). This large-scale study in South Korea establishes links across genes, environmental factors, and human health.
Findings here showed that an IF1 variant, known as rs3767303, was associated with lesser obesity among healthy men, but not among women. Likewise, the effects of this variant on measures such as body mass index, waist circumference, and blood glucose levels were different in men and women.
In contrast to women, men carrying the rs3767303 variant had higher blood levels of IF1.
Overall, the similarity between high IF1 in mice and naturally occurring high IF1 blood levels in people supports future human studies to better understand the role of IF1 as a biomarker for metabolic traits.
“Considering a rapid increase in the prevalence of obesity worldwide,” the scientists wrote, “our results provide novel insights into the development of sex-specific approaches to prevent and treat obesity and related metabolic diseases.”
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