Body Energy Homeostasis

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Many factors are involved in the control of food intake. Some of the most important factors controlling the amount of food that we eat include environmental factors such as food availability, the characteristics of the food itself (e.g., smell, taste, our eating habits, learned preferences and aversions) as well as other psychological and social factors, including our lifestyle. Although these psychosocial factors are extremely important to the food intake patterns of humans, this section will concentrate on the physiological factors, primarily the role of fat in food intake.

The regulation of body energy homeostasis, the balance between energy input and expenditure, is crucial to an animal's growth and survival. Complex central nervous system mechanisms have evolved to ensure that the animal's needs and its behavioral and physiological responses are coordinated. A starving animal, motivated by hunger, seeks out and ingests food when encountered. Simultaneously, mechanisms act to conserve body energy when possible (e.g., body temperature and activity may be decreased). In the long term, the interplay between the various environmental and physiological factors controlling energy input and expenditure determines the individual's body weight.

The importance of the hypothalamic brain area to the control of food intake and body weight has been known for at least 50-60 yr (Anand & Brobeck, 1951; Hetherington & Ranson, 1940). Initially, evidence demonstrated that the lateral hypothalamus (LH) and the ventromedial nucleus of the hypothalamus (VMN) were crucial. Lesion of the LH caused animals to lose body weight. Animals with a lesion of the LH decrease their food intake and increase their body temperature. Experiments suggested that the lesion of the LH reduced the animal's body weight "set point"; that is, when the animal's body weight was decreased by food deprivation prior to lesion of the LH, the normally observed undereating did not occur after the lesion, but, rather, the new low body weight was maintained. In contrast, lesion of the VMN caused animals to increase food intake and gain body weight. When an animal's body weight was increased prior to lesion of the VMN, the normally observed overeating did not occur after lesion, but, rather, the new elevated body weight was maintained. These results suggest that the "set point" is determined, at least in part, by hypothalamic mechanisms (Friedman & Stricker, 1976; Hoebel & Teitelbaum, 1966; Keesey & Hirvonen, 1997; Keesey, Mitchel, & Kemnitz, 1979; Keesey & Powley, 1975; Mrosovsky & Powley, 1977). Clearly, however, the "set point" can be influenced by various environmental and physiological factors, as evidenced by obesity. Interestingly, even "obese" humans appear to have a body weight set point (e.g., following a weight-loss regimen, most obese patients regain all of their lost weight within 9 yr) (Johnson & Drenick, 1977).

Evidence consistent with the idea of a body-weight "set point" is observed in animals with normal body weight as well. For example, like others (Keesey & Hirvonen, 1997),

Fig. 2. Effect of food restriction on subsequent food intake (A) and body weight (B) in rats. Following a 7-d baseline period, male Sprague-Dawley rats (n = 7) were restricted to 50% of their daily food intake for 12 d (to achieve a 15% decrease in body weight). Unlimited food was then made available and food intake and body weight was monitored for a further 21 d. * = p < 0.05, ** = p < 0.01, *** = p < 0.001 versus baseline.

Fig. 2. Effect of food restriction on subsequent food intake (A) and body weight (B) in rats. Following a 7-d baseline period, male Sprague-Dawley rats (n = 7) were restricted to 50% of their daily food intake for 12 d (to achieve a 15% decrease in body weight). Unlimited food was then made available and food intake and body weight was monitored for a further 21 d. * = p < 0.05, ** = p < 0.01, *** = p < 0.001 versus baseline.

we have observed that when animals are given free access to food after a period of food restriction, the loss in body weight is restored. Interestingly, overeating may only be evident during the first week following the return of free food access. See Fig. 2.

Fig. 3. Model showing mechanisms controlling body energy homeostasis. Major brain nuclei and central and peripheral pathways are shown. See text for abbreviations.

Today, other brain areas are known to be important to the control of food intake and body weight. Lesion of the arcuate nucleus (ARC) or PVN result in obesity (Bray, 1993; Dallman et al., 1993; Holzwarth-McBride, Hurst, & Knigge, 1976; Kirchgessner & Sclafani, 1988; Rothwell, 1990). One of the important factors contributing to obesity appears to be an increase in the activity of the hypothalamic-pituitary-adrenal axis. Adrenalectomy inhibits or prevents development of obesity subsequent to lesion of the ARC or PVN (Dallman et al., 1993). Other brain areas, such as the amygdala, area postrema (AP), NTS, parabrachial nucleus (PBN), DMV and frontal cortex are also involved (Bray & York, 1998; Dallman et al., 1993; Holzwarth-McBride et al., 1976; King et al., 1999; Kirchgessner & Sclafani, 1988; Ritter & Hutton, 1995; Woods, Seeley, Porte, & Schwartz, 1998). Disruption of the neural pathways between PVN, NTS, and DMV simulate aspects of the obesity caused by lesion of the VMN (Kirchgessner & Sclafani, 1988). Thus, these results are consistent with neural networks rather than neural centers controlling food intake and body weight. Of course, although many key brain areas have been identified, there is much to be elucidated in terms of determining the relevant pathways. See Fig. 3.

Glucose and fat are the two major sources of energy for the body. Early theories proposed that food intake was controlled by central mechanisms sensing changes in the level or utilization of these fuels. Mayer (1952; 1955) suggested that food intake was controlled by blood glucose levels or by levels of glucose utilization. Glucostats in the hypothalamus were thought to sense the changes in glucose levels. Some evidence suggests that a small decrease in plasma glucose precedes hunger and food intake in humans (Campfield & Smith, 1986).

Another theory, the "lipostatic" theory proposed by Kennedy (1950), suggested that food intake varied so as to maintain body fat stores (i.e., the "set point"). Changes in body fat stores, reflected in signals dependent on the size of those stores (e.g., blood levels of fatty acids), controlled food intake. Indeed, it has been shown that animals with lesion of the LH and VMN have pronounced disturbances in fat metabolism (Friedman & Stricker, 1976). Animals with a VMN lesion show increased fat storage such that circulating levels of the metabolic products of fat metabolism are decreased. It has been proposed (Friedman & Stricker, 1976) that it is this decreased availability of the metabolic products of fat metabolism that stimulate food intake.

Presently, in line with the idea that fat metabolism is crucial to body energy homeo-stasis, evidence suggests that peptides produced in the body and correlated with body fat mass are essential to the long-term control of food intake and body weight. Leptin is one such peptide. Leptin is the protein product of the ob gene. It is primarily produced in white adipose tissue, and the plasma level of leptin accurately reflects total-body adiposity (Friedman, 1997; Porte et al., 1998). It enters the brain from the circulation by a saturable transport mechanism (Friedman, 1997; Seeley & Schwartz, 1999; Woods et al., 1998). Leptin expression is stimulated by cortisol, insulin, and fasting and is attenuated by long-chain fatty acids (Houseknecht, Baile, Matteri, & Spurlock, 1998; Trayhurn, Hoggard, Mercer, & Rayner, 1999). It has been shown that central administration of leptin decreases body weight, primarily by causing the loss of fat (Chen et al., 1996; Halaas et al., 1997). Interestingly, although decreased food intake normally causes a reduction in energy utilization, this does not occur during administration of leptin. Indeed, body weight decreases during administration of leptin, even when food intake has returned to normal (Halaas et al., 1997).

The decrease in food intake caused by leptin is mediated by its actions on central peptidergic systems involved in food intake. For example, leptin stimulates peptidergic systems that inhibit food intake. Leptin stimulates corticotropin releasing factor (CRF) release in the PVN. CRF and urocortin, a newly discovered member of the CRF family, decrease food intake and increase energy expenditure (Richard, 1993; Rothwell, 1990; Weisinger et al., 2000). The decreased food intake caused by CRF/urocortin is mediated by CRF-R2 receptors (Smagin, Howell, Ryan, De Souza, & Harris, 1998; Spina et al., 1996), found in the VMN, amygdala, and PVN (Baram, Chalmers, Chen, Koutsoukos, & De Souza, 1997; Eghbal-Ahmadi, Hatalski, Avishai-Eliner, & Baram, 1997; Gray & Bingaman, 1996). It has been shown that the influence of leptin on food intake is blocked by a CRF receptor antagonist (Gardner, Rothwell, & Luheshi, 1998). CRF is thought to decrease food intake by its influence on the release of another peptide that inhibits food intake (i.e., oxytocin) (Olson, Drutarosky, Stricker, & Verbalis, 1991), or by its ability to decrease gastric emptying (Tache, Maeda-Hagiwara, & Turkelson, 1987). The increase in energy expenditure caused by CRF/urocortin has been attributed to their activation of the sympathetic nervous system (Arase, York, Shimizu, Shargill, & Bray, 1988; Rothwell, 1990; Smagin et al., 1998; Spina et al., 1996). The influence of leptin and CRF on food intake and body weight are clearly very similar and it seems likely that the actions of leptin are, at least in part, mediated via a system involving CRF and its receptors.

In addition, leptin acts to inhibit the activity of peptidergic systems that stimulate food intake. Leptin receptors have been found on many of the peptidergic neurons thought to increase food intake and body weight. Such neurons are found throughout the brain and include the melanin-concentrating hormone (MCH)-containing neurons of the LH, the neuropeptide Y (NPY)-containing neurons of the ARC and VMN, and the galanin-containing neurons of the PVN (Hakansson, de Lecea, Sutcliffe, Yanagisawa, & Meister, 1999; Meister, 2000). Much seems to be known about how these various peptidergic neurons influence food intake. MCH is synthesized in the LH and MCH-containing neurons project to various brain areas involved in energy balance. Stimulation of MCH (Chambers et al., 1999) pathways causes increased food intake. NPY is found in neurons in the ARC that project to the PVN, LH, and NTS. Stimulation of NPY pathways is followed by increased food intake, lipogenesis, and decreased sympathetic nervous system activity and energy expenditure in brown fat (Billington & Levine, 1992; Grundemar & Hakanson, 1994; Levine & Billington, 1997; Richard, 1995; White, 1993). Stimulation of food intake by NPY is thought to be mediated by neurons expressing MCH, via an ARC-LH pathway (Broberger, De Lecea, Sutcliffe, & Hokfelt, 1998). NPY neurons appear to be more responsive to changes in carbohydrate metabolism than to fat metabolism (Leibowitz, 1995). Galanin-expressing neurons and neurons with galanin receptors are found in many brain areas involved in food intake such as LH, PVN, and amygdala (Merchenthaler, Lopez, & Negro-Vilar, 1993). Activation of galaninergic neurons that project from the anterior PVN to the median eminence (ME) causes increased intake and accumulation of fat (Leibowitz, 1995; Leibowitz & Alexander, 1998). Interestingly, not only does leptin prevent food intake caused by NPY, MCH, and galanin, but also leptin appears to block the formation of these peptides (i.e., leptin decreases hypothalamic NPY, MCH, and galanin gene expression) (Sahu, 1998). The decrease in MCH caused by leptin is, at least in part, mediated by a-melanocyte stimulating hormone (aMSH). Leptin increases expression of aMSH, a peptide that acts on neurons with melanocortin-4 (MC-4) receptors and stimulation of these receptors decreases MCH (Broberger, 1999; Hanada et al., 2000). aMSH may also be involved in the decrease in food intake caused by CRF (Rothwell, 1990).

Leptin also influences body weight by interacting with peptides that control short-term food intake (i.e., peptides that affect meal size and/or meal frequency). Secretion of the gut-peptide cholecystokinin (CCK) produces short-term satiety. However, although CCK can decrease meal size, meal frequency is increased such that body weight is not altered (West, Fey, & Woods, 1984). One of the mechanisms by which CCK decreases food intake is by decreasing gastric emptying (Moran & McHugh, 1982). Interestingly, it has been shown (Matson, Reid, Cannon, & Ritter, 2000) that when leptin (given centrally) and CCK (given peripherally) are given simultaneously, body-weight loss is greater than that observed when leptin is given alone. The synergy between leptin and CCK cannot be explained by decreased food intake alone. Presumably, increased energy expenditure is involved. It should be noted that most of the peptides that influence food intake also influence, inversely, the activity of the sympathetic nervous system controlling thermogen-esis in the brown adipose tissue. For example, NPY increases food intake and decreases activity of the sympathetic nervous system, whereas CRF decreases food intake and increases activity of the sympathetic nervous system (Bray, 1993).

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