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Obesity Drugs Could Mimic the Effects of a Cigarette in the Snow

Credit: delihayat/iStockphoto

Credit: delihayat/iStockphoto

By Jack Pryor, Stephanie Simonds & Michael Cowley

A study has produced rapid weight loss by activating cold and nicotine receptors that stimulate the body to burn fat while also suppressing appetite.

The expanding number of overweight people across the globe has increased the demand for new and effective anti-obesity drugs. While some weight loss drugs have fallen out of favour with consumers, others have been removed from sale, either because they’re not effective or because they have dangerous side-effects. Examples of the latter include amphetamines, fenfluramine and dinitrophenol (DNP).

DNP was originally produced as an explosive for artillery shells during the First World War. In 1933 Maurice Tainter, a Stanford University pharmacologist, discovered that when DNP is ingested it leads to rapid fat loss – as much as 1.5 kg per week. This revelation soon gained DNP widespread popularity as a weight loss aid, but it soon became clear that taking it was really dangerous

Weight loss drugs work by reducing food intake, reducing calorie absorption and/or increasing metabolic rate. DNP induces weight loss by massively raising metabolic rate, hijacking oxidative phosphorylation and causing all but a few cells to convert calories into heat rather than store it as adenosine triphosphate (ATP).

Respiration takes place in three stages: glycolysis, the citric acid cycle and oxidative phosphorylation. The latter is the most efficient form of respiration, yielding the most molecules of ATP per calorie. DNP reduces this efficiency, putting the body in an energy deficit. This stimulates the body to burn fat.

DNP is an effective weight loss drug but it causes systemic heat production when taken in high doses. With vital organs unable to cope with temperatures as high as 45°C, DNP kills people by cooking them from the inside out.

DNP is now banned as a weight loss drug in many countries, including Australia, the USA and the UK, but it is still easy to find online and people continue to die from it.

The mechanism by which DNP causes weight loss is similar to the metabolic processes that keep us warm in cold weather. Here, low temperature is sensed by cold receptors and this information is signalled to the brain. The central nervous system responds by stimulating brown adipose tissue (BAT) to increase its production of an “uncoupling protein” that elicits the same thermogenic effect as DNP.

The crucial difference here is that heat production is restricted to BAT, which is only found beneath the collarbone and down either side of the spine. This tissue-specific effect helps maintain body temperature without any risk of hyperthermia.

BAT is called “brown” adipose tissue because it contains high densities of mitochondria, which are brown. Oxidative phosphorylation occurs only in mitochondria, so BAT has the capacity to burn a lot of calories when it receives the appropriate signal from the central nervous system.

As BAT has the capability to increase metabolic rate, it is being touted as a promising target for future weight loss drugs. Hence scientists are trying to create new drugs that stimulate BAT to produce heat, even in the absence of a cold environment.

In addition to being activated by low temperatures, cold receptors can be stimulated by chemicals. In the same way that capsaicin in chilies activates heat receptors, menthol activates the cold receptor to elicit the cooling sensation associated with mint.

Breath mints won’t be solving the obesity crisis any time soon as menthol doesn’t activate the cold receptor sufficiently to stimulate BAT thermogenesis. However, another compound called icilin is 200 times more potent than menthol in its activation of the cold receptor, and as such is a promising compound for the fight against fat.

A good rule of thumb is that if a drug has no side-effects it probably has no primary effect either. It follows that if a drug has an effect, it likely has some side-effects. Any swimmer will tell you that a side-effect of being cold is hunger.

Icilin may well induce weight loss through increased metabolic rate, but this occurs at the expense of increased food intake, which is clearly a counterproductive side-effect of a potential weight loss drug. With this in mind, we have recently assessed the weight loss effects of icilin given in combination with another drug that diminishes food intake. In this case we used the nicotine receptor agonist dimethylphenylpiperazium (DMPP). Our study was recently published in Nature Communications (https://goo.gl/yuWPy9).

Cigarettes suppress appetite because nicotine activates nicotinic acetylcholine receptors throughout the central nervous system. For instance, hypothalamic POMC neurons (which express nicotinic receptors) increase their electrical activity under positive energy states, such as after a meal. This activation is just part of the convoluted neural feedback loop responsible for the regulation of food intake.

POMC neurons are activated by a number of hormones and neurotransmitters, including insulin, but they are also activated by nicotine. Hence nicotine is an appetite suppressant, so for some people a cigarette is a valid alternative to lunch.

To recap, icilin elevates metabolic rate by stimulating BAT to produce heat, but icilin also increases appetite. DMPP counter­acts the latter effect by activating nicotinic receptors in the brain – including receptors on hypothalamic POMC neurons.

Our study tested the effects of icilin and DMPP in obese laboratory mice. Crucially, the physiological effects of each were investigated both in isolation and in combination with the other compound.

We found that giving either icilin or DMPP alone reduced body weight by ~3% in 4 days. However, when given together the reduction in body weight was more than the sum of their parts, with mice losing around 9% in the same timeframe. The US Food and Drug Administration demands a minimum of 5% weight loss within a year for weight loss drugs, so these results are really promising.

Another interesting observation of this study was that administration of DMPP improved blood glucose tolerance, even at doses that didn’t affect body weight. Glucose tolerance describes the ability of the body to absorb glucose after a meal; poor glucose tolerance is a major risk factor for type 2 diabetes. If this research is to be translated into the production of a drug for humans, and indeed if results from clinical trials are in line with those observed here, then the fight against obesity may have gained a novel pharmaceutical that can both stimulate weight loss and reduce the probability of developing diabetes.

Addiction is cause for concern with any compound that modulates the nicotinic system, as is the prospect that systemic activation of cold receptors could make patients feel like they were sunbaking in the snowfields. However, as we continue to unpack the complexities of metabolic physiology, we will discover the molecular idiosyncrasies of cold and nicotinic receptors alike. This understanding will enable those in the business of drug discovery to adjust compounds to maximise the benefits and minimise the side-effects.

Moreover, dosage is crucial when it comes to drugs. Hopefully the therapeutic window for this combination is sufficiently wide so that it can stimulate weight loss while avoiding any undesirable side-effects – which is where DNP goes wrong.

The obesity epidemic is huge. Across the globe more than 1.4 billion adults are overweight; of these, 104 million are obese. Obesity and its related diseases cost 2.8 million lives and US$2 trillion every year.

This research is in its earliest days, but the results are clearly encouraging. We need more new and effective drugs in addition to improved education and rigorous public health policy if we are going to help the global population live longer and healthier lives.


Jack Pryor, Stephanie Simonds and Michael Cowley are physiologists from the Monash Biomedicine Discovery Institute.