What is Energy Homeostasis?

Homeostasis is "the tendency of a system, especially the physiological system of higher animals, to maintain internal stability, owing to the coordinated response of its parts to any situation or stimulus that would tend to disturb its normal condition or function." (dictionary.com).

So in the context of an organism, "energy homeostasis" then refers to the bodies control of its own energy or the balance between food intake and energy expenditure. We use energy via daily activity, but also via a 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).When this system is out of balance, various metabolic conditions can 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 for "normal" living.

Do genes play a role in BMI?

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 increased 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 as well. 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.

To the right you see a db/db mouse which was found to have lost the hormone leptin (picture taken from Wikipedia). These animals have around 50-60% of their body mass as pure fat (Cox & Powley 1977 J Comp Physiol Psychol)

Peripheral and central pathways

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.

Picture created in BioRender.com.

Leptin deficiency in mammals compared to fish

In a stunning study, Sadaf Farooqi found that found a girl who gained weight excessively from 4 months of age, likely because she felt constantly hungry. Treatment with leptin cured the obesity (Farooqi et al 1999). The figure to the left is from a 3 year old boy who weighed 42kg and after leptin administration weighed 32kg at 7 years old (see Farooqi and O'Rahilly 2014). While this particular condition is exceedingly rare, the core genes found to be involved in energy homeostasis are conserved between humans and mice and indeed in all vertebrates including amphibians, birds and fish.

However, there are some very divergent life histories represented amongst vertebrates!

From a plethora of studies we know that the biochemical pathways underlying energy homeostasis at a cellular level, meaning gycogenolysis, gluconeogenesis, glycolysis, Krebs cycle, fatty acid oxidation et cetera are incredibly well conserved at the protein level, and "for biology there remains the great and nagging problem of how to explain in mechanistic terms the incredible diversity and obvious adaptedness of living things on this planet" (Hochachka, 1988).

While the genes underlying the control of energy homeostasis are well conserved across all vertebrates, the actual details appear to differ between life histories and species. In companion animals, particularly in dogs there have been studies finding similar pathways (reviewed by Wallis and Raffan, 2020). In farm animals, particularly the involvement of the melanocortin receptor 4 (MC4R) appears to lead to weight gain changes but the relationship is no so immanently evident (Switonski et al., 2013). Research in monotremes finds that the relationship between plasma leptin and body adiposity is weak to non existent (Nicol, 2017). Further, the relationship between leptin and obesity becomes even more tenuous as we start looking into fish (Londraville et al., 2014) or birds (Friedman-Einat and Seroussi, 2019). So what happened and what role do these energy homeostasis genes which are conserved at a genetic level play across vertebrates?

On the flipside of the obesity coin is hunger or the control of hunger. Indeed, during food deprivation the body needs to conserve energy and one mechanism to do this is by decreasing costly processes such as reproduction and growth amongst others. Indeed, during fasting, circulating levels of hormones like growth hormone (GH), follicle stimulating hormone (FSH) and luteinizing hormone (LH) drop together with circulating levels of leptin and in mice, even though animals are fasting the circulating hormone levels can be rescued by central leptin administration (Ahima et al., 1996). In mice as well as humans, leptin is secreted in proportion to body fat and therefore this means that as body fat levels and leptin levels drop, so do GH, FSH and LH and thereby the energy costly processes these hormones mitigate. It is therefore more likely, that leptin mitigates fasting biology and prevents energy expenditure when energy levels are low (Flier and Maratos-Flier, 2017). In this line of thought, Barbara Kahn showed that leptin can activate muscular energy stores in mice (Minokoshi et al., 2002).

In several fish species, leptin levels actually increase in response to fasting and it is feasible that this signal drives energy recruitment in fish (Londraville et al., 2014; Deck et al., 2017).