Far from being an innocent response to insulin resistance, hyperinsulinemia drives weight gain and metabolic disruptions, a new study says. Researchers who manipulated mice genes to limit their ability to make insulin found that lowinsulin mice did not become obese on a high-fat diet but actually burned more energy, with their white adipose tissue acting akin to brown fat.

“It’s a very clever experiment,” said C. Ronald Kahn, MD, a prominent insulin and diabetes researcher at Harvard Medical School who was not involved in the study. “I think it is a significant finding because it does challenge our concepts of what is the role of hyperinsulinemia in metabolic syndrome.”

Insulin Genes

Researchers at the University of British Columbia devised an approach to lowering insulin levels that avoids the pitfalls of previous studies that used drugs, with their unavoidable side effects. Th e researchers exploited the fact that mice have two insulin genes, and therefore four possible alleles. Insulin gene 1 is specific to the pancreas. Insulin gene 2 is like the human insulin gene, present in the pancreas and also in organs such as the brain and thymus.

Mice with both genes knocked out make no insulin and die in infancy, but those with just a single allele function relatively normally. Th e researchers controlled the amount of insulin their mice could make by knocking out the insulin 2 gene entirely, and then creating a line who were missing one allele of gene 1 and therefore genetically limited in the amount of insulin they could produce. Th e researchers then compared how the mice with both alleles vs. a single allele of the pancreas-source gene fared when fed a high-fat diet. That diet normally leads to obesity, hyperinsulinemia, diabetes, and other complications, and the mice with two alleles gained weight as expected.

But the mice with only one allele did not. In addition to avoiding obesity despite consuming a similar amount of calories, they had less inflammation and less liver fat than the other mice. “These mice were healthy across the board; they didn’t accumulate fat in their livers, or any of their other not normally fat-storing tissues, like the regular high-fat mice do,” said lead author James Johnson, PhD, an associate professor of medicine at the University of British Columbia in Vancouver. “Their glucose levels are surprisingly normal given the fact they were missing three of the four insulin genes.”

New Finding on Energy Expenditure

The mice ate similar amounts of food, which raised the question of where the extra calories went in the mice that did not gain weight. To explore the molecular mechanisms involved in this phenomenon, the researchers designed a real-time polymerase chain reaction miniarray of 45 key metabolic, inflammatory, and insulin target genes. They were surprised to find that one of the major sets of genes upregulated in the white adipose tissue of the haploid mice increased the activity of uncoupling proteins—mitochondrial proteins associated with burning energy in brown adipose tissue. This process has been referred to as “browning” of white fat.

“High insulin programs the white fat to really hold onto its nutrients and not burn any of them,” Johnson told Endocrine News. “If you can reduce the hyperinsulinemia, you have an upregulation of these uncoupling proteins, which will burn energy and increase energy expenditure, with no difference in food intake.”

These findings on insulin’s effect on energy balance make the study stand out, said Kahn: “I think they are the first people to say it in quite this way. There are other people who have said that the hyperinsulinemia might be bad because it makes more insulin resistance, but this is something different. [The idea] that hyperinsulinemia actually changes energy expenditure is very new. Most people would say that high insulin promotes obesity because it causes more fat storage directly. But [Johnson] is saying it’s not causing more fat storage directly, but what it is doing is decreasing energy expenditure, and allowing the energy to be stored.”

Not a New Idea

Th is idea that insulin is a driver of obesity has had its champions since the 1970s, but this is the most direct evidence and clearest demonstration of a mechanism yet, according to Robert Lustig, MD, a pediatric endocrinologist at the University of California San Francisco and member of the Endocrine Society Obesity Task Force. Lustig has been convinced of high insulin’s detrimental role since treating pediatric patients who had obesity caused by hypothalamic tumors. Because the brains of these patients could not sense leptin, their bodies went into a starvation response, and constantly over-released insulin to store energy.

Lustig’s team treated the patients with the acromegaly drug ocreotide, which is used to treat pituitary tumors but also reduces pancreatic insulin secretion. “When we were successful in reducing their insulin release, the patients lost weight and started to feel better. But even more importantly, they started exercising spontaneously and their resting energy expenditure went up, suggesting that energy expenditure was tied to energy intake through insulin,” said Lustig, who has been in the spotlight recently after release of his popular book on obesity (see sidebar).

Insulin Resistance Paradox

Johnson said that his experience in working with the pituitary leads him to question the generally accepted reasoning about insulin resistance: “We were taught as neuroendocrinologists that if there is too much of a certain hormone or neurotransmitter, the receptor for that hormone or neurotransmitter gets desensitized, which is that hormone’s resistance. Diabetes is the only field in endocrinology where they think the opposite, where they think that the resistance happens first.”

He cites research in flies and worms, which has shown that when researchers knock out a cluster of genes that control aging and leanness and stimulate insulin, the animals with reduced insulin are lean and live twice as long. “The people who study worms and flies are tuned in to the idea that you can have excess insulin, and if you bring that down it is beneficial for the organism. But clinical endocrinologists are used to thinking of insulin as a good guy because in the complete absence of insulin you have diabetes. It can be very difficult to think of it as both a good guy and potentially a bad guy when there is too much,” Johnson said.

The study, which Johnson calls “the first evidence that insulin itself is required for weight gain in vivo,” appeared in the December 5 edition of Cell Metabolism.

—Seaborg is a freelance writer in Charlottesville, VA, and a regular contributor to Endocrine News.

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