Lab
Michel Lab
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Statement of Research Interest
Energy homeostasis is the concept that we need to balance food intake with energy expenditure. We use energy daily activity but also via the basal metabolic rate (the energy it takes to keep the body functioning in a resting state) and the thermic effect of food (the energy it takes to metabolize food and make its nutrients and energy available) (see Figure 1).
When this system is out of balance, various metabolic diseases follow which collectively pose a huge societal burden. Obesity follows from an increased hunger drive, while a lack of appetite leads to anorexia and cancer cachexia. Each of these is comorbid with a variety of other conditions, predominantly type 2 diabetes with obesity, but reproductive issues are also comorbid with both ends of the scale - obesity as well as anorexia. Therefore a good balance between food intake and expenditure is critical.
One might posit that eating too little or too much is largely a cultural and behavioural burden - too much high-calorie food, too little exercise whether due to increase work times or decreased interest; and these undoubtedly have a large impact. However, our genetics have a surprisingly large effect on how we balance our energy intake. A recent estimate by Sir Stephen O'Rahilly is that "genetics explains most (probably around 65%) of weight variation between individuals" (Speakman and O’Rahilly 2012). The first glimpses on what genes underlie these effects came from mouse breeding experiments in the sixties at Jackson Laboratories in the US. Several monogenic mouse strains were found to have obesity but also comorbidities such as diabetes, and these were aptly named the 1) obese, 2) diabetic, 3) agouti (also has a coat colour phenotype), 4) fat and 5) tubby mice (Naggert et al., 1997). The genes causing these phenotypes were found starting in the nineties and research in this field has exploded since then. Simply, the hormone leptin is produced in adipose tissue in proportion with fat mass and signals via AgRP and POMC neurons to melanocortin neurons that enough energy is present in the periphery. When we fast, the leptin (from the greek leptos - thin) levels drop and this gets translated by the melanocortin neurons in the hypothalamus of the brain into hunger. Mice that lack leptin for example (the obese mouse strain) are profoundly hyperphagic because the brain constantly thinks that the animal is starving! Consequently these animals are severely obese with more than half of their body fat bein adipose tissue. Administration of leptin corrects the severe obesity, both in mice as well as in people. In a stunning study, Sadaf Farooqi found that found a girl who gained weight excessively from 4 months of age, and who was constantly hungry. Treatment with leptin cured the obesity (Farooqi et al 1999). While this particular condition is exceedingly rare, the core genes found to be involved in mouse energy homeostasis are conserved to humans and play similar roles in people.
But not only are these genes conserved across mammals but across all vertebrates. I work on energy homeostasis in the Zebrafish. The zebrafish is an organism whose early development has been extensively studied in the past decades. The genome has been sequenced and labs across the world have contributed to a stunning toolbox to study zebrafish biology. We have established several mutant lines in leptin, leptin receptor and AgRP as well several marker lines in oder to visualize these circuits in early development.
While the core genes and mechanisms are conserved between mice, fish and men, key differences exist in the detail. One focus of the lab is to build a roadmap to metabolic control in zebrafish in order to understand which aspects of energy homeostasis are functionally conserved and which differ. Strengths lie in both answer. Where they are functionally conserved, the fish can be utilized as a model system and the full power of fish genetics in forms of forward genetics screens can be utilized to study the conserved endophenotype.
Other aspects of metabolism are not so well conserved such as leptin biology. The hormone in mice is only expressed in white (Zhang et al 1994) while in fish it is usually not found in adipose tissue in most species studied to date. We found that overfed zebrafish with leptin or Leptin Receptor mutations do not become obese in contrast to mice with leptin or leptin receptor mutations, however their phenotype lies in glucose regulation. In mice with this mutation, obesity and diabetes are comorbid. This opens up fascinating questions - if leptin does not signal fat levels to the brain, what does? What is the mechanism of glucoregulation by leptin in fish and can further insight be capitalized on to study why in humans type 2 diabetes is sometimes comorbid with obesity but not always?
The long-term goals of this research are threefold 1) ameliorate abnormal homeostasis patterns (with impact across animal species), 2) gain insight into the evolution of biological diversity and 3) drive insight into growth behavior in farm animals (domestication as an ecological niche).
For further information and background to non-mammalian vertebrate energy homeostasis, please see the recent research topic I edited: https://www.frontiersin.org/research-topics/4907/comparative-studies-of-energy-homeostasis-in-vertebrates
When this system is out of balance, various metabolic diseases follow which collectively pose a huge societal burden. Obesity follows from an increased hunger drive, while a lack of appetite leads to anorexia and cancer cachexia. Each of these is comorbid with a variety of other conditions, predominantly type 2 diabetes with obesity, but reproductive issues are also comorbid with both ends of the scale - obesity as well as anorexia. Therefore a good balance between food intake and expenditure is critical.
One might posit that eating too little or too much is largely a cultural and behavioural burden - too much high-calorie food, too little exercise whether due to increase work times or decreased interest; and these undoubtedly have a large impact. However, our genetics have a surprisingly large effect on how we balance our energy intake. A recent estimate by Sir Stephen O'Rahilly is that "genetics explains most (probably around 65%) of weight variation between individuals" (Speakman and O’Rahilly 2012). The first glimpses on what genes underlie these effects came from mouse breeding experiments in the sixties at Jackson Laboratories in the US. Several monogenic mouse strains were found to have obesity but also comorbidities such as diabetes, and these were aptly named the 1) obese, 2) diabetic, 3) agouti (also has a coat colour phenotype), 4) fat and 5) tubby mice (Naggert et al., 1997). The genes causing these phenotypes were found starting in the nineties and research in this field has exploded since then. Simply, the hormone leptin is produced in adipose tissue in proportion with fat mass and signals via AgRP and POMC neurons to melanocortin neurons that enough energy is present in the periphery. When we fast, the leptin (from the greek leptos - thin) levels drop and this gets translated by the melanocortin neurons in the hypothalamus of the brain into hunger. Mice that lack leptin for example (the obese mouse strain) are profoundly hyperphagic because the brain constantly thinks that the animal is starving! Consequently these animals are severely obese with more than half of their body fat bein adipose tissue. Administration of leptin corrects the severe obesity, both in mice as well as in people. In a stunning study, Sadaf Farooqi found that found a girl who gained weight excessively from 4 months of age, and who was constantly hungry. Treatment with leptin cured the obesity (Farooqi et al 1999). While this particular condition is exceedingly rare, the core genes found to be involved in mouse energy homeostasis are conserved to humans and play similar roles in people.
But not only are these genes conserved across mammals but across all vertebrates. I work on energy homeostasis in the Zebrafish. The zebrafish is an organism whose early development has been extensively studied in the past decades. The genome has been sequenced and labs across the world have contributed to a stunning toolbox to study zebrafish biology. We have established several mutant lines in leptin, leptin receptor and AgRP as well several marker lines in oder to visualize these circuits in early development.
While the core genes and mechanisms are conserved between mice, fish and men, key differences exist in the detail. One focus of the lab is to build a roadmap to metabolic control in zebrafish in order to understand which aspects of energy homeostasis are functionally conserved and which differ. Strengths lie in both answer. Where they are functionally conserved, the fish can be utilized as a model system and the full power of fish genetics in forms of forward genetics screens can be utilized to study the conserved endophenotype.
Other aspects of metabolism are not so well conserved such as leptin biology. The hormone in mice is only expressed in white (Zhang et al 1994) while in fish it is usually not found in adipose tissue in most species studied to date. We found that overfed zebrafish with leptin or Leptin Receptor mutations do not become obese in contrast to mice with leptin or leptin receptor mutations, however their phenotype lies in glucose regulation. In mice with this mutation, obesity and diabetes are comorbid. This opens up fascinating questions - if leptin does not signal fat levels to the brain, what does? What is the mechanism of glucoregulation by leptin in fish and can further insight be capitalized on to study why in humans type 2 diabetes is sometimes comorbid with obesity but not always?
The long-term goals of this research are threefold 1) ameliorate abnormal homeostasis patterns (with impact across animal species), 2) gain insight into the evolution of biological diversity and 3) drive insight into growth behavior in farm animals (domestication as an ecological niche).
For further information and background to non-mammalian vertebrate energy homeostasis, please see the recent research topic I edited: https://www.frontiersin.org/research-topics/4907/comparative-studies-of-energy-homeostasis-in-vertebrates
Lab Members
| Lakshminarasimha, Amrutha Bagivalu Graduate Student |