Why are obese mice so easy to chase?

Dysfunctional signaling in the brain makes obese mice less active


Obesity is accompanied by a lack of motivation/desire to exercise. This has lead to the idea that lack of exercise leads to obesity. A new study challenges this by showing that both “lazy” and “active” mice gain weight on a fatty diet [1]. All mice on high fat diet become obese and then move around less than mice fed on standard chow. The researchers go on to show that the lack of motivation to exercise that accompanies obesity may well be brought about by neuronal changes in the regions of the mouse brain that respond to movement.


The physical inactivity that accompanies obesity is frustrating for those wanting manage their own weight as well as those who want support a near and dear one who does [2,3]. A better understanding of where this seeming ‘lack of motivation’ to exercise comes from may help design better intervention strategies. Previous studies suggest that obese animals and humans may have defects in dopamine signaling in a region of the brain that controls movement behaviours with the result that they may find physical activity less rewarding [4,5]. However, does lack of exercise cause weight gain?

What did they do and find?

Mice were fed standard chow (lean) or high fat diet (obese) for 18 weeks. Mice become both obese and less active when fed a high fat diet. The researchers of this study wanted to understand if the mice became fat because they were less active. To their surprise they found that low activity and weight gain occurred hand in hand but were not cause and effect. The weight gain however was correlated to the high fat diet.

So what was causing the lower activity in obese mice? There is a bit of the brain called the striatum which is responsible for movement and is disrupted in disorders such as Parkinson’s. There are neurons in this region of the brain that are sensitive to the neurotransmitter dopamine and fire (get activated) during movement. The authors of this study reasoned that perhaps it is this region of the brain that is responsible for inactivity in obese mice.

First they looked for components of dopamine signaling, the levels of dopamine itself and the dopamine receptors which when present on neurons allows them to respond to dopamine. They found that the striatum of obese mice had Dopamine Receptors of a specific kind (D2R receptors) which showed decreased binding while the levels dopamine itself and the other receptor for dopamine was the same in lean and obese mice. This reduction in dopamine 2 Receptor binding did not correlate with weight gain but was correlated with movement loss.

So would lean mice also move less if they had lower binding D2Rs?

Indeed, in genetically modified mice that lacked D2R receptors in the striatal region – lower activity levels were observed even in lean mice. This showed that neuronal changes underlie lower activity levels in obese mice.

To probe this further the researchers measured the activity of neurons in the striatum by inserting an electrode in the brain of live obese and lean mice. These recordings showed that during movement there was less overall firing in the brain of obese mice.

In order to test if these brain regions and neurons were indeed responsible for the lower activity observed in obese mice, the researchers used a special set of mice. These mice are specially modified to express a molecule that is usually produced by active Dopamine signaling via D2R binding (Gi) coupled to an opiod receptor only in the neurons of the striata that naturally express D2R. This allows Gi to be uniquely switched on by use of a synthetic chemical (Salvinorin B). When Gi is artificially produced by the D2R expressing neurons of the striatum both lean mice and obese mice become more active.

Reducing the D2R levels artificially in the neurons of the striatum results in mice with lower activity levels however these mice were not more susceptible to weight gain. Nor are mice with low D2R binding in the beginning of the diet predisposed to weight gain.

Take homes from the study

Experiments on animal behaviour are difficult and sometimes hard to extend beyond specific cases because genetic and environmental effects play a large role in shaping observed behaviour and this study is no different. These data convincingly argue that in mice, obesity is accompanied by and not caused by lack of activity. It also gives us a perspective on how integrated an animal’s body and mind are. At the very least it makes us think that in combating obesity, a role for the mind cannot be ignored.


1. Basal Ganglia Dysfunction Contributes to Physical Inactivity in Obesity. Danielle M. Friend, Kavya Devarakonda, Timothy J. O’Neal, Miguel Skirzewski, Ioannis Papazoglou, Alanna R. Kaplan, Jeih-San Liow, Juen Guo, Sushil G. Rane, Marcelo Rubinstein, Veronica A. Alvarez, Kevin D. Hall, Alexxai V. Kravitz, Cell Metab. 2017 Feb 7

2. The mysterious case of the public health guideline that is (almost) entirely ignored: call for a research agenda on the causes of the extreme avoidance of physical activity in obesity. Ekkekakis P, Vazou S, Bixby WR, Georgiadis E, Obes Rev. 2016 Apr;17(4):313-29

3. Exercise does not feel the same when you are overweight: the impact of self-selected and imposed intensity on affect and exertion, P Ekkekakis and E Lind, International Journal of Obesity (2006) 30, 652–660

4. Reward mechanisms in obesity: new insights and future directions. Kenny PJ. Neuron. 2011 Feb 24;69(4):664-79.

5. Obesity and addiction: neurobiological overlaps (Is food addictive). Volkow ND, Wang GJ, Tomasi D, Baler RD. Obes Rev. 2013 Jan;14(1):2-18.

6. Do Dopaminergic Impairments Underlie Physical Inactivity in People with Obesity? Kravitz AV, O’Neal TJ, Friend DM, Front Hum Neurosci. 2016 Oct 14;10:514. eCollection 2016.

7. Increases in Physical Activity Result in Diminishing Increments in Daily Energy Expenditure in Mice. Timothy J. O’Neal,, Danielle M. Friend, Juen Guo, Kevin D. Hall, Alexxai V. Kravitz Curr Biol. 2017 Feb 6;27(3):423-430.

An Interview with Dr. Alexxai V. Kravitz

1. What is causing the change in dopamine signaling in the neurons responsive to movement in obese mice? Do you have more insights into this from your study of Parkinson’s?

This is a great question, but unfortunately one that we don’t know the answer to. Parkinson’s disease is caused by the death of neurons that make dopamine, and we looked at dopamine neurons in obese mice and learned that they were not dying. So in that way, the mechanism underlying the changes in dopamine signaling in obese mice is very different than with Parkinson’s disease. This is a good thing, as it would frankly be scary if a diet high in fat were causing the death of dopamine neurons! Instead, we observed dysfunction in a specific dopamine receptor (a protein that detects dopamine) in obese mice. We’re looking into what exactly is causing the dysfunction of this receptor, but unfortunately we do not currently know.

2. You data does show that mice become both obese and move less on high fat diet, but which bit convinces you that the “laziness” is because of the obesity? Can they not be two parallel outcomes of a high fat diet? If yes, then would a high fructose or high calorie diet lead to a similar outcome?

Let me clarify here – I don’t think the *weight* of the mice is causing the laziness, I believe dysfunction in their dopamine receptors is causing their laziness [More on this in Ref. 6]. And both this dysfunction and weight gain can be caused by the high fat diet. So in that say, yes, they can be two parallel outcomes of the high fat diet. To answer your second question, I’m not sure if other high calorie diets can cause the same dysfunction. This would be a great follow up experiment!

3. In your paper, you describe the limitations of human studies that have measured Dopamine signalling and its links to obesity. Can you tell us a bit more about what the challenges are?

To date there have been a handful of studies that have compared D2 receptor levels in people with obesity vs. normal weight, and a minority have reported dysfunction in D2Rs in people with obesity. It is not clear why some studies have reported lower levels of D2 receptors, while most have not. However, measuring dopamine receptor levels in humans is difficult. The only technique for measuring receptor levels in humans is PET scanning, a technique where a radioactive tracer is injected and the brain is scanned for the location where the tracer binds. If more tracer binds, it is assumed there are more “available” receptors in that brain area. However, this technique can be affected by many factors, including what other transmitters are bound to that receptor. If internal levels of dopamine are higher during the scan, for instance, the amount of a radio-tracer that binds to a dopamine D2 receptor will be lower. The complexity increases when we consider how many things can alter dopamine levels throughout the day, which include caffeine use, food intake, and sleep. These are some of the challenges that face clinical research. Animal studies are less likely to incur these sources of variance, and have more consistently reported decreases in D2 receptors in association with obesity.

4. Are the changes in the striatum reversible, by forced exercise for example or are there natural molecules that could restore Gi signaling?

There are no known ways to reverse these changes, but there is also very little research on this. There is a small amount of evidence in rats that forced exercise increases D2 receptor levels, but this is very preliminary and has not been replicated, nor studied in humans. This idea of how to alter D2 receptor levels is an extremely important concept for future research!

5. Are there common themes about obesity and lower activity levels that have emerged from animal studies and how would you extend them, if at al, to humans? For instance, you say mice and rats are different, then would you expect people to be more similar to mice than rats? Why?

It is very difficult to extend results from mice to humans, so I will be cautious on this one. However, there are some concepts from animal work that are relevant to humans. Many researchers have noted that animals voluntarily over-eat high fat diets, and that this leads to weight gain and obesity. While the specific macronutrient (fat vs. carbs vs. protein) content of human diets is the subject of a lot of debate when it comes to human obesity, it is fair to say that diets that induce over-eating will lead to obesity. Typically, foods that induce over-eating are highly palatable, such as junk foods that pack large numbers of calories into small volumes. While people are all different from one another, understanding the foods that a specific person overeats will inform what is likely to cause that person to gain weight.

As another concept that I believe is relevant to human s, in our study we reported that physical inactivity did not correlate with weight gain in mice. That is, we examined inactive mice that lacked D2 receptors, and found that they gained weight at the same rate as normal active mice. We also examined the natural variation of activity levels of normal mice and did not note any relationship here either. This seems to counter the conventional wisdom that inactivity should cause weight gain. However, this conventional wisdom is based largely on correlations between obesity and inactivity, rather than causal tests of this hypothesis. We all know that correlation does not imply causation, but it is very easy to get caught in this trap. In fact, in causal tests, the contribution of exercise alone (without changes in diet) to weight loss in humans is fairly small, generally resulting in 3-5 pounds of weight loss over the first year. This is consistent with our conclusions in mice. Studies in mice can help us understand at a mechanistic level why changes in activity (both increases and decreases) don’t translate into large changes in body weight [More on this in Ref.7].

6. In their natural habitats animals such as mice and rat consume high fat diets. Do you think your results would hold in wild rodents instead of lab reared ones, especially if they were allowed to interact freely with each other and the environment?

Wow, what a great question! We use lab mice, which have been bred in captivity for many decades. This is somewhat similar to studying domesticated dogs vs. wild dogs. And in many ways, our laboratory mice are quite different from wild mice. However, I believe that even wild mice would become inactive on a high fat diet. The association between obesity and inactivity has been seen in many species including humans adults, children, non-human primates, domesticated cats and dogs, rats, and mice. When an association occurs across so many species of animals, I think it is likely that it would extend to wild mice as well as laboratory mice. This would be a great student project to find some wild mice and test!

A novel pathway of Brain Drain

Two studies provide a new map of waste management systems in the mouse brain


Snap-shot of the study

How is the brain protected from pathogens or chemicals? For a long time, it was thought that the brain is protected by barriers, such that it is impermeable even to immune cells (that could protect it) and to most chemicals (including drugs that need to act in the brain) (1,2). More recently it has become clear that cells of our immune system do constantly survey the brain (3). How do these cells get in and out? In the July 2015 issues of Nature and JEM, two groups report the discovery of an extension of the lymphatic system into the brain.


 If the circulatory system can be likened to the nutrient supply system of the body, the lymphatic system is somewhat like drainage system, collecting fluid, large molecules and white blood cells from tissues, thus recycling blood components. The lymphatic system includes the tonsils, spleen and lymph nodes and extends throughout the body. This system contributes to fluid clearance, pathogen recognition and mounting of an immune response to pathogens. So it is indeed surprising that there was an arm of this system in the brain that we had no idea about until about a month ago. Two recent papers describe a lymphatic vessel network in the membrane covering of the brain that carries the fluid in which the brain floats (the cerebrospinal fluid) and drains into the deep cervical lymph nodes (5,6).

What did they do and find?

In both of these studies using mainly imaging based techniques, the authors identify vessels in the mouse brain which they call the meningeal lymphatic vessels using molecular markers that tag lymphatic endothelial cells.

In the dura mater, the covering of the brain, T-cells (a kind of immune cells) are found scattered throughout. However, Louveau et al. noticed many T-cells lining the Superior Sagittal Sinus (SSS). Surprisingly, these cells were not seen in significant numbers in the lumen of (read, inside) the SSS. This suggested that these T-cells could be residing in a separate compartment like blood vessels or lymphatic vessels. The authors ruled out blood vessels and used specific markers (read, tags – namely Prox-1, Podoplanin and VEGFR3) to demonstrate that these were indeed lymphatic vessels containing lymphatic endothelial cells. The vessel containing the T-cells was positive for Lyve-1 (tags lymphatic vessel) and was clearly visible as a channel running close to the SSS. These results confirmed that this vessel was indeed a lymphatic endothelial compartment.

Last year, Aspelund et al. reported the surprising finding that the eye also contains a lymphatic-like vessel, the so-called Schlemm canal (4). While studying the eyes of mice whose lymphatic vessels were labelled with flourescent markers, they found the brain lymphatics in the adjacent tissues. The lymphatics were present along blood vessels in various parts of the dural membranes even at the base of the skull with several exit paths through the same openings used by cranial nerves. Further, they were also able to show a critical role for the VEGF receptor signalling pathway  in the formation of these lymphatic vessels. In the absence of these vessels, consistent with their role in clearance and management of waste, large molecules did not get cleared from the brain (6).

Both groups explored if these are functional lymphatic vessels by injecting intravenously with a fluorescent dyes or, special minute(nano) particles, to track the flow of fluids from the brain tissue through the different compartments. This experiment showed that the vessels carry the brain fluid (read, cerebrospinal fluid or CSF) into the deep cervical lymph nodes.

These two studies have important implications for conditions in which there is pathological aggregation of proteins in the brain (Alzheimer’s) and also on how the immune system keeps a check on the brain in health and disease.

An interview with Dr. K Alitalo, Dr. A Louveau

Q. How do you see this discovery will help to shed light on previously unanswered questions of our understanding of the central nervous system?

(Dr. K Alitalo) This is an important discovery that will enable scientists to look at neurological diseases from an entirely new standpoint. The vessels may be key in explaining some features of diseases that could not previously understood.

Q. We also came across a recent publication by Louveau et al., published in journal Nature which talks about a similar lymphatic system. Is this the same system that you show in your publication

( Dr. K Alitalo) It is indeed the same system. We did a more thorough job at characterizing it as we found out that the vessels extend to dural venous sinuses, meningeal arteries, cranial nerves and the cribriform plate. Louveau et al. used a methodology that only enabled the discovery of the vessels in the superior parts of the skull along dural venous sinuses.

Q. Do you think advances in the imaging techniques and the availability of well defined markers was the only reason for such a late discovery of this system? Are there any other possibilities that could have contributed to delay in this discovery?

( Dr. K Alitalo) Probably the greatest challenge for the visualization of meningeal lymphatic vessels has been the adjacent osseous bone. The need for decalcification is, in many respects, problematic for tissue analysis. Most importantly, I think both discoveries were enabled by advanced imaging technologies, which have transformed the world of traditional 2D tissue sections into 3D. In our study, the discovery was enabled by the previous generation of lymphatic-specific fluorescent reporter mice in which the lymphatic vessels can be visualized as they are in tissues by fluorescent microscopy, without the need for any processing.

Q. Do you think similar lymphatic vessel could be present in humans, what are the technical challenges you see in establishing it?

( Dr. K Alitalo) The techniques already exist, so it is just a matter of time when researches will perform this work. The only problem is that endothelial cells become autolytic soon after death.

Q. Your study clearly shows the role of lymphatic vessels in draining macromolecules out of the brain. What potential implications would this have on human health conditions like infectious diseases, disorders like Alzheimer’s and tumor metastasis?

( Dr. K Alitalo) The brain lymphatics may become structurally and functionally altered in infectious diseases. This needs to be evaluated in the context of pathogenesis of such diseases. – Alzheimer’s disease is characterized by the pathological accumulation of amyloid beta into the brain tissue. Proper meningeal lymphatic vessel function could perhaps protect against Alzheimer’s disease by clearing pathological amyloid beta from the brain parenchyma. Perhaps we can boost such clearance with our technology. Brain tumors rarely metastasize into cervical lymph nodes. However, when this happens, it has been unknown how the metastases arise. The meningeal lymphatic vessels are likely to represent the missing link.

Q. How do you see this discovery will help to shed light on previously unanswered questions of our understanding of the central nervous system?

(Dr. A Louveau) This discovery is changing an established paradigm described decades ago, that the brain is an immuno privileged organ because, at least in part, of the lack of classical lymphatic drainage. What we demonstrate is that the brain possesses a classical lymphatic drainage, but the brain remains immunologically unique. We will have to change the way we see the brain when we want to address diseases that have immunological factors.

Q. We also came across a recent publication by Aspelund et al., published in Journal of Experimental Medicine which talks about a similar lymphatic system. Is this the same system that you show in your publication?

(Dr. A Louveau) Yes, the study recently published by the group of Kari Alitalo confirmed our study and shows similar results to the one we published.

Q. Do you think advances in the imaging techniques and the availability of well defined markers was the only reason for such a late discovery of this system? Are there any other possibilities that could have contributed to delay in this discovery?

(Dr. A Louveau) The development of the imaging techniques and the fairly recent description of specific markers to identify lymphatic endothelial cells (early 2000) are certainly major factors in the late discovery of this system. One other reason is the unique location in the dura mater, a region of the meninges usually discarded when people study the brain (because this layer remains attached to the skull).

Q. In the paper you mentioned similar lymphatic vessel could be present in humans as well, what are the technical challenges you see in establishing this?

(Dr. A Louveau) We think that the challenge will not be technical but highly depend on the quality of the tissues collected. Most human tissue collection have been fixed for month to years rendering immunostaining challenging. Collecting more recently collected tissue should help, but lymphatic vasculature appear to be sensitive structure.

Q. What are the potential implications of this discovery, on human health conditions like infectious diseases, disorders like Alzheimer’s or Schizophrenia and tumor metastasis?

(Dr. A Louveau) We think that the meningeal lymphatic system might play a role in every neurological disease with a strong immune component, including the ones you are mentioning. In Alzheimer disease, the blockade of the meningeal lymphatic might be an initial event before the accumulation of unfolded protein in the brain. In the case of brain tumor, the meningeal lymphatic system might be used by the tumor to prevent its attack by the immune system. But all of this remains hypothetical and the function of the meningeal lymphatic system will have to be studied in all of those diseases.

Q. In one of your interviews you have mentioned that your discovery would require modifications in the textbooks. Could you elaborate more on the changes that you envisage?

(Dr. A Louveau) If you open a neuroscience textbook right now, you’ll read that the brain is devoid of a lymphatic system, therefore contributing to its immune privilege. Our discovery, more so if it extends to humans, proves that this statement is wrong and that the brain, like every other organ possesses a lymphatic system.


1. “The blood-brain barrier: an engineering perspective.” Andrew D. Wong et al., Front Neuroeng., 2013

2. “The gut immune barrier and the blood-brain barrier: are they so different?” Richard Daneman and Maria Rescigno, Immunity, 2009

3. “Immune surveillance in the central nervous system.”  Shalina S Ousman and Paul Kubes, Nat Neurosci., 2012

4. “The Schlemm’s canal is a VEGF-C/VEGFR-3-responsive lymphatic-like vessel.” Aleksanteri Aspelund et al., J Clin Invest. 2014

5. “Structural and functional features of central nervous system lymphatic vessels.” Antoine Louveau et al., Nature. 2015

6.“A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules.” Aleksanteri Aspelund et al., J Exp Med., 2015