Disturbances of Regulation of Energy Homeostasis

The incidences of both obesity and type 2 diabetes mellitus are rising at epidemic proportions and have emerged as a major threat to human health in the late twentieth and early twenty-first century. Growing evidence suggests that nutrient and hormonal signals converge and act directly on brain centers, leading to changes in fuel metabolism. Many newly discovered molecules that are proposed to play an active role in the physiology and pathophysiology of energy homeostasis have changed our understanding of obesity and metabolism and have attracted the attention of many researchers who strive to investigate and characterize the mechanisms underlying energy homeostasis. The purpose of this information is to summarize POH's current understanding of peripheral pathways regulating energy homeostasis and to outline new targets for the treatment of obesity, metabolic disorders, and associated co-morbidities.

Afferent signals to the brain convey information via exogenous and/or environmental factors influencing energy homeostasis, nutrients or metabolic factors, and finally hormonal signals regarding long- or short-term energy availability. These inputs can be classified into three distinct types, namely, neural environmental, nutrient/metabolic, and endocrine signals.

In modern societies of affluence, high palatability and oro-sensory properties of certain foods, in combination with environmental influences that promote a sedentary way of life, promote a positive energy balance and development of obesity. Mood and other signals that affect “emotional eating” and are being processed by complex neural circuits have a significant effect on these environmental signals and also regulate energy homeostasis.

Sensors expressed in hypothalamic neurons such as ion channels and surface enzymes act as direct sensors of nutrients such as carbohydrates and lipids and activate intracellular second messenger pathways to regulate energy homeostasis. The role of nutrients and metabolic signals to regulate energy homeostasis is discussed in detail below.

Hormones are released from peripheral endocrine organs, including the white adipose tissue (leptin), pancreas (insulin, amylin), stomach (ghrelin), and intestine (cholecystokinin, CCK). Hormonal signals such as the adipose-tissue-secreted hormone leptin and the pancreatic hormone insulin regulate the long-term metabolic status and body’s energy stores whereas other signals such as gastrointestinal hormones convey information on the amount or composition of the food entering the gastrointestinal tract.

Short-term regulation of feeding is also regulated by neural afferent signals from the periphery which are activated by a combination of mechanical stimuli (distension, contraction) , chemical stimuli (presence of nutrients in the gut lumen), and neuro-humoral stimuli (gut hormones, neurotransmitters)  and are mainly conveyed via the vagus nerve to important CNS target centers such as the hypothalamus and the brain.

Development of obesity and type 2 diabetes could ensue from alteration in the balance in the nutrient-activated mechanisms/nutrient-sensing pathways. It has been proposed that circulating factors, e.g., lipids, glucose, or protein products, that are generated in proportion to body fat stores and/or nutritional status act as signals to the brain, eliciting changes in energy intake and expenditure. A prolonged period of excessive food intake has been proposed to lead to weight gain and insulin resistance by activating nutrient-sensing pathways which process the signal for the availability of nutrients at central sites (hypothalamus) as well as directly in peripheral tissues (muscle and fat).

All these pathways may either act independently or converge to decrease expression of proliferator-activated receptor co-activator 1 (PGC-1) α and β , key co-activators of PPAR α , γ , and δ , leading to mitochondrial dysfunction and reduced energy expenditure, all of which enhance the risk for obesity and insulin resistance Dietary fat is the most energy-dense macronutrient in the diet . Short-term feeding studies have indicated that dietary fat might be used more efficiently than carbohydrates and thus it accumulates as body fat. When these short-term feeding studies are extended to 4 days, however, no difference in stored energy is observed. It has thus been suggested that carbohydrate intake, unlike fat intake, is regulated. The rationale underlying the promotion of low-fat diets is largely based on the belief that dietary fat is positively associated with body fat through the high energy density of fat and enhanced palatability of high-fat foods. However, traditional recommendations of fat restriction have been shown to have a negligible effect on long-term weight loss whereas low-fat diets may also not offer any benefit in terms of reducing the risk of cardiovascular diseases. Thus, further studies are needed to clarify the role of dietary fat in regulation of energy homeostasis.

According to the first law of thermo-dynamics, the total energy of a system plus the surroundings remains constant. Obesity can result, therefore, from a relative increase in energy intake (food) compared to EE. The regulation of EE and its role in body weight homeostasis has not been very well studied to date. Potent physiologic mechanisms maintain body weight within a narrow “set point” and regulate energy balance with accuracy in most humans, as demonstrated by under- and overfeeding studies. Certain thermogenic mechanisms, such as leptin-induced increases in EE and diet-induced thermogenesis, a critically important anti-obesity mechanism as per studies in rodents, have evolved in mammals to allow burning up of excess energy. Human studies suggest that increased sympathetic nervous system (SNS) activity, decreased parasympathetic nervous system activity, and an inferred form of physical activity known as non-exercise activity thermogenesis (NEAT) lead to an increase in EE in overfeeding states and obesity. However, many more studies are needed to determine the importance of thermogenic, anti-obesity mechanisms in humans.

EE can be categorized into obligatory (basal) and adaptive (facultative) thermogenesis. Obligatory EE includes all processes that are involved in the maintenance of basic metabolic and physiologic processes, including the maintenance of ion gradients, muscle tone, digestion, and blood flow (standard metabolic rate). Adaptive thermogenesis includes cold and diet-induced thermogenesis. For example, although thyroid hormone (TH) is required for up to 30% of standard metabolic rate, adaptive increases in TH are required for normal cold-induced thermogenesis. Physical activity can also have long-lasting effects on resting metabolic rate. Approximate contributions of the various EE components are resting metabolic rate (70%), physical activity (20%), facultative (10%), with physical activity representing the most variable component.

The role of diet composition on body weight is an area of controversy in the field of obesity research. Diet composition can affect body weight in individuals who are in energy balance. In a recent review, Astrup et al. found that body weight is reduced slightly as dietary fat content of the diet is lowered in individuals who were in energy balance. Reducing dietary fat without food restriction may affect both energy intake and EE in small ways, since voluntary intake may be lower with low- vs. high-fat diets. Increasing dietary carbohydrate and reducing dietary fat could also be expected to produce a slight increase in the thermic effect of food, since carbohydrate produces more thermic effect than fat does, but this remains to be conclusively shown. The impact of high- vs. low-glycemic diets as well as of protein diets on energy balance is still the focus of intensive research efforts. Diet composition during negative energy balance Diet composition may have different effects depending on whether subjects are in energy balance or whether they are in positive or negative energy balance. During equivalent negative energy balance, there might be little difference in altering the fat/ carbohydrate ratio of the diet and there seems to be similar body weight and body fat loss with high- and low-fat diets when total energy intake is fixed at a level below energy requirements. However, there are several reports of differences in weight loss with high- and low-fat diets when energy intake is not fixed, suggesting that diet composition may affect satiety or hunger during dieting. A recent meta-analysis concluded that non-energy-restricted, low-carbohydrate diets were at least as effective as low-fat diets over a period of 1 year. Lowering dietary fat has little impact during negative energy balance. Therefore, in general, low-fat diets have not been found to lead to greater weight loss than diets higher in fat content.

During positive energy balance, diet composition can have a relatively larger effect on energy balance. Studies have shown that excess energy is efficiently stored in the body regardless of its source, but it has been proposed that excess energy from dietary fat is stored more efficiently than excess energy from carbohydrates. This area is of significant interest and the focus of intensive research efforts.

Thyroid hormones (TH; including T 4 and T 3 ) play a significant role in regulating EE. Thyroid hormones mediate ~30% of basal thermogenesis and stimulate numerous anabolic and catabolic pathways. Low TH levels in response to dietary restriction are associated with reduced EE during weight loss and act to resist body weight change in obesity. These changes in TH levels are also associated with changes in EE and SNS. All these alterations are to a certain degree due to falling leptin levels in response to weight loss, but the extent to which falling leptin mediates the alterations in TH in response to food deprivation and whether leptin administration in replacement doses would improve weight loss maintenance remain to be seen.