New Danish research improves understanding of how the hypothalamus and the rest of the brain control how much we eat.
NAD+, ATP, leptin, NAMPT, SIRT1, nicotinamide, POMC and FK866.
This may sound technical, but all these molecules decisively influence how much food we eat.
A new Danish research project shows that FK866, a selective inhibitor of NAMPT (nicotinamide phosphoribosyltransferase), inhibits the NAD+ (nicotinamide adenine dinucleotide)-generating pathway in the hypothalamus, and this affects whether we feel hungry.
The research results indicate a possible target for combating obesity.
“This study is a step towards understanding how various substances influence the hypothalamus, regulating whether people feel hungry or full and influencing whether they become overweight. The more we understand this system, the better we can develop specific compounds that may be used to treat obesity by inhibiting people’s hunger,” says Jonas Thue Treebak, Associate Professor, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.
The study was recently published in Acta Physiologica.
Two neurons determine whether we feel hungry or full
The hypothalamus has two types of neurons, POMC and AgRP. Leptin affects POMC, and ghrelin affects AgRP.
Leptin is secreted from adipose tissue and makes us feel full; ghrelin is secreted in the stomach and makes us feel hungry.
Essentially, the balance between how leptin affects POMC and how ghrelin affects AgRP determines how hungry we feel.
The enzyme SIRT1 is involved in regulating this balance, and previous research has shown that manipulation of SIRT1 levels in the hypothalamus can either increase or decrease hunger.
NAD+ further influences SIRT1, and this is where the new study is relevant.
“Our starting-point was to look further back in the chain and examine the factors that affect the levels of NAD+ in the brain. NAMPT is an enzyme that turns vitamin B3 into NAD+, and we therefore asked what happens when we influence this enzyme, which controls the activity of SIRT1 and thereby the feeling of hunger,” explains Jonas Thue Treebak.
FK866 made mice eat less
The researchers experimentally inhibited NAMPT in mouse brains by injecting FK866 very precisely through a cannula directly into the third ventricle of the brain, which is connected to the hypothalamus.
They then observed the mice and noted how much they ate. The mice ate less when FK866 was injected into their brains.
The researchers also investigated whether the mice lost their appetite because the FK866 injections caused anhedonia, but the experiments showed that the mice did quite well but were just less hungry.
Experiment confirmed hypothesis
The researchers placed a swab with the scent of female mice into the cage with male mice and then observed their behaviour.
If the mice felt unwell, they would not be interested in the scent of female mice, but the males were just as interested in this scent as control males without the FK866 injections.
The researchers also administered ghrelin to mice. This normally stimulates hunger and causes mice to eat more, but the FK866 injections inhibited the hunger that would otherwise have arisen.
“The experiment confirmed our hypothesis. We expected that inhibiting NAMPT with FK866 would reduce the levels of NAD+ and reduce food intake and we observed this in the mice,” says Jonas Thue Treebak.
Overweight people cannot be treated with FK866
As one element of a larger puzzle, this new study has potentially great perspectives.
Thinking that FK866 can be used to fight the current obesity epidemic might be tempting but is unrealistic.
FK866 is toxic to the body’s cells, and giving it to people who are overweight is difficult to defend.
But researchers now understand better the mechanisms they can influence to potentially reduce obesity.
“We believe that manipulating the metabolism of NAD+ in POMC and AgRP may correct any imbalance between these neurons and that this may inhibit hunger. We already know today that people who become leptin resistant have more difficulty in feeling full and that people eat more if they are unusually sensitive to ghrelin. This balance needs to be restored,” says Jonas Thue Treebak.
Treating obesity with vitamin B3
Jonas Thue Treebak explains that the researchers are already examining various ways of influencing the system that determines whether we feel hungry or full.
The researchers are investigating various types of vitamin B3, the substrate NAMPT uses to make NAD+. One is nicotinamide riboside.
This can be taken orally and could become an interesting approach for combating obesity if it can restore a healthy balance of NAD+ in the neurons of the hypothalamus and thereby counteract increased feelings of hunger.
Unfortunately, experiments so far have not yielded positive results.
“We previously gave people nicotinamide riboside for 12 weeks but found no effects on the participants’ weight, body composition or metabolism. We may not have given the vitamin to the participants for long enough, or it needed to be given differently to be effective. We will examine these things in the future to improve understanding of how to manipulate this system,” says Jonas Thue Treebak.
“Fasting- and ghrelin-induced food intake is regulated by NAMPT in the hypothalamus” has been published in Acta Physiologica. Several authors are employed at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.
