October 2, 2013 | 1
Please welcome this month’s Scicurious Guest Writer, Zarja Muršič!!
Imagine it is Sunday morning. The day when you may finally be free in the morning and have time to go get your king-size breakfast, the one you probably should eat every day. You sit down with a big ‘ol Denver omelet, or maybe you love oatmeal with fruit, or perhaps a delicious French baguette with butter, marmalade, or honey. You feel like you might be able to eat a lot at first, but after a couple of pieces, you’ve had enough. Though you see the beauty of the food in front of you, and it still tastes good, something is saying stop.
Did you ever wonder what tells your brain that your stomach has had enough?
It is obvious that the reason does not come from the outside. It’s not in the bombardment of popular media, which is competing to give you advice on what and how much to eat for your breakfast. There is another reason why we do not overeat, a signal coming to us from our own bodies. Mice and other animals don’t read magazines or watch TV, but in most cases, they don’t overeat. Mice, and men, in most cases know when enough is enough, and have bodily signals to stop eating. A hormone, leptin, is the key.
Leptin, a protein hormone, is made and secreted by white adipose tissue or body fat, and circulates in the blood. It acts on many peripheral tissues and can also cross into the brain. Scientists first discovered leptin because of its activity within the hypothalamus to suppress food intake, reduce appetite, and decrease body fat (4-6, 12). The hypothalamus is a part of the central nervous system, located at the “floor” of the brain of the brain, above the brain stem and below the thalamus.
It affects many body functions. One of them is homeostasis. Homeostasis refers to all the processes that regulate an organism’s internal environment. It makes us feel cold or warm, awake or sleepy. One of the things homeostasis also involves is the regulation of energy, how much food we take in, and how much we use. That involves leptin, the protein taking care that your body gets just enough of that breakfast and assures its energy levels are in balance.
Just how important is leptin? Studies of genetically modified strains of mice with deficiency in production of leptin, and so without the ability to reduce food intake, are prone to obesity and diabetes (8). These mice have a genetic defect in fat cells, which prevents them from secreting leptin, and without leptin, they don’t have the signal to stop, so they keep eating, and get very obese.
So, maybe you are halfway through your omelet, or that big bowl of oatmeal, and your body begins to produce leptin, signaling you have had enough. This may be the whole story of your Sunday breakfast, but the leptin has not yet finished its work. Maybe you didn’t make that omelet yourself, but bought it at a little breakfast place down the road. If you remember where that breakfast place is, you might be able to go back. And leptin plays a role here as well. Our bodies are quite efficient and will turn one hormone to many uses. In case of leptin – if the hormone can do one thing, it can be adapted to do another as well, and in this case, leptin plays a role in cognition.
Scientists started digging deeply into the brain and discovered that leptin receptors, proteins on cell surface where hormones can bind, are not only present in the hypothalamus to regulate appetite, but can be found in some other parts of the central nervous system including the cortex and hippocampus. These brain areas play a role in our cognitive processes, such as memory and learning. Some researchers even discovered leptin mRNA (messenger RNA which will be used to make leptin) and protein in some regions of central nervous system (11), which means leptin is made and released, not only from fat cells, but in the brain as well.
Breakfast, appetite, leptin, brain and cognition; what does leptin have to do with cognition, our ability to think? In that, lies a story from the past.
Over our history, our diet, our daily way of living, hunting, and searching for food, had a great role in shaping our cognitive capacity and brain evolution (3). If leptin is engaged in some of the cellular mechanisms that enable our cognitive capabilities, such as memory and learning, that is also a positive advantage for an animal. Leptin could allow us to develop strategies to find and remember places where food is to be found (13). This leads us to many connections between our present-day diet and the way we think and remember.
Links between leptin and cognition start early in the development of the central nervous system. Leptin can effect how big our brains grow, an important task, as a less developed brain might mean problems with solving cognitive tasks. Important evidence comes from the rodent models of leptin deficiency. Not only do they become obese, they also have smaller brains. When researchers added leptin back, brain weight increased (1). These alterations in brain development were even evident in utero, mice in utero with leptin deficiency had smaller brains, and with the leptin replacement, brain size during development increased (17). Clearly, leptin helps make brains big. Similarly, in humans with the leptin deficiency, adding leptin back in leads to large changes in brain structure (10).
In older populations, there is a correlation between low leptin levels and impaired cognition, something that severely impacts older adults (7, 12). Furthermore, while low levels of leptin might mean smaller brains, high levels of leptin could help save neurons from an untimely death. In particular, studies have shown that leptin can induce neurotrophic signals that promote survival and growth of neurons in neurodegenerative diseases associated with aging, including Parkinson’s and Alzheimer’s disease (16). Increasing leptin could help save neurons and reverse the symptoms of these diseases. Leptin has already been tested for use in rodent models of neurodegenerative diseases and it may be workable treatment that can slow down the progression of diseases (2, 16).
So leptin controls our appetite, and it also controls the size of our brains. What about those receptors for leptin that are in other areas of the brain? Maybe they play some role in memorizing where have you found the delicious breakfast?
Receptors for leptin have been found in cortical regions and the hippocampus. Both of these are brain areas usually associated with learning, memory, cognitive function, motivation, neuroprotection and more. Research on rodent models of leptin receptor deficiency, the case where there is leptin, but there is no protein on the cell surface where leptin could bind to, exhibit behavioral problems with solving spatial memory tasks. Development of crucial cellular electrical processes that underlie behaviors such as learning and memory are impaired (9). The cellular mechanisms involved with learning and memory are long-term potentiation (LTP) and depression (LTD). They are involved in synaptic plasticity. When LTP and LTD are at work it means the connections between neurons will change. LTP strengthens the connections at synapses between neurons whereas LTD weakens this links. LTP leads to formation of stronger memories on the cellular level. On the other hand LTD leads to weakened neuronal connections and cellular “memories”. Therefore, the lack of leptin or its action could lead to memory formation problems.
In a study where researchers administered leptin into the hippocampus, LTP was enhanced and with it the cellular mechanism of memory formation was also propagated (13). There is also a human example of a leptin deficient individual with reduced cognitive performance at baseline that exhibited an improvement in neurocognitive tests after the leptin treatment (15).
So leptin may be able to enhance learning and memory. Then does this mean it’s a cognitive enhancer? Just wait a second! This is almost a perfect hormone; it reduces your appetite and at the same time it makes you smart. But not so fast. It may only work with people with medical deficiencies. In one of the presented studies (13) researchers administered leptin to rats in different concentrations. Results showed that lower dosage actually promotes spatial learning and memory formation, whereas higher concentration has opposite effect. It inhibits spatial learning and memory formation. Giving leptin on the top of normal leptin might cause more problems than it solves. There are still many unanswered questions regarding leptin action and function. Things are rarely black and white in biology.
(Leptin deficient mice at left. Source)
Leptin acting within other non-hypothalamic areas of the brain may provide a unique mechanism linking obesity and diabetes to impaired cognitive function. Leptin deficiency, when the hormone is not present in the organism and leptin resistance, when there is no successful leptin signaling to the target cells, both lead to obesity and may also produce impaired cognition. In the first case there is no signal to prevent from overeating as well as no help from leptin in the cellular processes of learning the memory formation (LTP). In the case of leptin resistance (12), the leptin signal does not come to the target cells or it isn’t recognized by receptors (18); therefore it is just like there is no signal. Studies in animals with leptin resistance showed also difficulties in cognitive functions (9, 12).
Eating maintains the body’s energy balance and may also prime the brain to facilitate learning and memory with the help of leptin (13). Normal leptin levels in our body, can therefore prevent us from overeating, and at the same time promote learning and memory formation. All of these may have an important rule in animals when searching for food. After finding and eating a meal it is important for animals to memorize where it was for next time.
Maybe all this talk about breakfast gave you an appetite, and you probably know where your fridge is. Before you go there to make yourself a snack, listen up, and see if leptin is saying to you: “You are full, you are not yet hungry!” Instead of getting angry at it (you really wanted that cupcake), try to appreciate its existence, since it is also one of the proteins that enable you to learn, memorize and use all sort of cognitive functions you might have.
1. Ahima R. S., Bjorbaek C., Osei S. & Flier J. S. (1999). Regulation of neuronal and glial proteins by leptin implications for brain development. Endocrinology, 140(6): 2755-2762.
2. Fewlass D. C., Noboa K., Pi-Sunyer F. X., Johnston J. M., Yan S. D. & Tezapsidis N. (2004). Obesity-related leptin regulates Alzheimer’s Abeta. Faseb J, 18:1870–1878.
3. Gomez-Pinilla F. (2008). Brain foods: the effects of nutrients on brain function. Nat Rev Neurosci, 9(7): 568-578.
4. Harvey J. (2007). Leptin regulation of neuronal excitability and cognitive function. Curr Opin Pharmacol, 7(6-3): 643-647.
5. Harvey J. & Ashford M. L. J. (2003). Leptin in the CNS: much more than a satiety signal. Neurophramacol, 44: 845-854.
6. Harvey J., Solovyova N. & Irving A. (2006). Leptin and its Role in Hippocampal Synaptic Plasticity. Prog Lipid Res, 45(5): 369-378.
7. Holden K. F., Lindquist K., Tylavsky F. A., Rosano C., Harris T. B. & Waffe K. (2009). Serum leptin level and cognition in the elderly: Findings from the Health ABC study. Neurobiol Aginig, 30(9): 1483-1489.
8. Kenney P. J. (2013). The food addiction. Scientific American, 309(3): 34-39.
9. Li X. L., Aou S., Oomura Y., Hori N., Fukunaga K. & Hori T. (2002). Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents. Neuroscience, 113: 607-615.
10. Matochik J. A., London E. D., Yildiz B. O., Ozata M., Caglayan S., DePaoli A. M., Wong M. L. & Licinio J. (2005). Effect of leptin replacement on brain structure in genetically leptin deficient adults. J Clin Endocrinol Metab, 90(5): 2851-2854.
11. Morash B., Li A., Murphy P. R., Wilkinson M. & Ur E. (1999). Leptin gene expression in the brain and pituitary gland. Endocrinology, 140: 5995-5998.
12. Morrison D. F. (2009). Leptin signaling in brain: A link between nutrition and cognition? Biochim Biophys Acta, 1792(5): 401-408.
13. Oomura Y., Hori N., Shiraishi T., Fukunaga K., Takeda H., Tsuji M., Matsumiya T., Ishibashi M., Aou S., Li X. L. Kohno D., Uramura K., Sougawa H., Yada T., Wayner M. J. & Sasaki K. (2006). Leptin facilitates learning and memory performance and enhances hippocampal CA1 long-term potentiation and CaMK II phosphorylation in rats. Peptides, 27: 2738-2749.
14. Ozata M., Ozdemir I. C. & Licinio J. (1999). Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab, 86(10): 3686-3695.
15. Paz-Filho G. J., Babikian T., Asarnow R., Esposito K., Erol H. K., Wong M. L. & Licinio J. (2008). Leptin replacement improves cognitive development. PLoS ONE, 3(8): e3098.
16. Signore A. P., Zhang F., Weng Z., Gao Y. & Chen J. (2008). Leptin neuroprotection in the central nervous system: Mechanism and therapeutic potentials. J Neurochem, 106(5): 1977-1990.
17. Udagawa J., Hashimoto R., Suzuki H., Hatta T., Sotomaru Y., Hioki K., Kagohashi Y., Nomura T., Minami Y. & Otani H. (2006). The role of leptin in the development of the cerebral cortex in mouse embryos. Endocrinology, 147: 647–658.
18. Tartaglia, L. A. (1997). The Leptin receptor. J Biol Chem, 272: 6093-6096.
Zarja is currently an MSc student in Cognitive Science and Structural and Functional Biology at University of Ljubljana, Slovenia. She is curious about the world around her and interested in the intersection of cognitive science and evolutionary biology. She tweets as @piskotk. If you understand Slovene, a strange language that uses dual, you are welcome to follow her blog Piškotarna.