Energy Expenditure, Fat Oxidation, and Body Weight Regulation: A Study of Metabolic Adaptation to Long- Term Weight Change

The perinatal environment plays a crucial role in programming many aspects of adult physiology. Myriad stressors during pregnancy, from maternal immune challenge to nutritional deficiency, can alter long-term body weight set points of the offspring. In light of the increasing concern over body weight issues, such as obesity and anorexia, in modern societies and accumulating evidence that developmental stressors have long-lasting effects on other aspects of physiology (e.g., fever, pain), we explored the role of immune system activation during neonatal development and its impact on body weight regulation in adulthood. Here we present a thorough evaluation of the effects of immune system activation (LPS, 100 μg/kg ip) at postnatal days 3, 7, or 14 on long-term body weight, adiposity, and body weight regulation after a further LPS injection (50 μg/kg ip) or fasting and basal and LPS-induced circulating levels of the appetite-regulating proinflammatory cytokine leptin. We show that neonatal exposure to LPS at various times during the neonatal period has no long-term effects on growth, body weight, or adiposity. We also observed no effects on body weight regulation in response to a short fasting period or a further exposure to LPS. Despite reductions in circulating leptin levels in response to LPS during the neonatal period, no long-term effects on leptin were seen. These results convincingly demonstrate that adult body weight and weight regulation are, unlike many other aspects of adult physiology, resistant to programming by a febrile-dose neonatal immune challenge.

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Predicting metabolic adaptation, body weight change, and energy intake in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00559.2009 ◽

2010 ◽

Vol 298 (3) ◽

pp. E449-E466 ◽

Cited By ~ 114

Author(s):

Kevin D. Hall

Keyword(s):

Body Weight ◽

Energy Expenditure ◽

Energy Intake ◽

Weight Change ◽

Initial Conditions ◽

Whole Body ◽

Metabolic Adaptation ◽

Model Parameters ◽

Body Weight Change ◽

Fuel Selection

Complex interactions between carbohydrate, fat, and protein metabolism underlie the body's remarkable ability to adapt to a variety of diets. But any imbalances between the intake and utilization rates of these macronutrients will result in changes in body weight and composition. Here, I present the first computational model that simulates how diet perturbations result in adaptations of fuel selection and energy expenditure that predict body weight and composition changes in both obese and nonobese men and women. No model parameters were adjusted to fit these data other than the initial conditions for each subject group (e.g., initial body weight and body fat mass). The model provides the first realistic simulations of how diet perturbations result in adaptations of whole body energy expenditure, fuel selection, and various metabolic fluxes that ultimately give rise to body weight change. The validated model was used to estimate free-living energy intake during a long-term weight loss intervention, a variable that has never previously been measured accurately.

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Regulation of Body Weight in Humans

Physiological Reviews ◽

10.1152/physrev.1999.79.2.451 ◽

1999 ◽

Vol 79 (2) ◽

pp. 451-480 ◽

Cited By ~ 190

Author(s):

Eric Jéquier ◽

Luc Tappy

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Energy Expenditure ◽

Weight Regulation ◽

Body Weight Regulation ◽

Human Obesity ◽

Tissue Mass ◽

Leptin Receptors ◽

Adipose Tissue Mass ◽

Plasma Leptin

The mechanisms involved in body weight regulation in humans include genetic, physiological, and behavioral factors. Stability of body weight and body composition requires that energy intake matches energy expenditure and that nutrient balance is achieved. Human obesity is usually associated with high rates of energy expenditure. In adult individuals, protein and carbohydrate stores vary relatively little, whereas adipose tissue mass may change markedly. A feedback regulatory loop with three distinct steps has been recently identified in rodents: 1) a sensor that monitors the size of adipose tissue mass is represented by the amount of leptin synthesized by adipose cells (a protein encoded by the ob gene) which determines the plasma leptin levels; 2) hypothalamic centers, with specific leptin receptors, which receive and integrate the intensity of the signal; and 3) effector systems that influence the two determinants of energy balance, i.e., energy intake and energy expenditure. With the exception of a few very rare cases, the majority of obese human subjects have high plasma leptin levels that are related to the size of their adipose tissue mass. However, the expected regulatory responses (reduction in food intake and increase in energy expenditure) are not observed in obese individuals. Thus obese humans are resistant to the effect of endogenous leptin, despite unaltered hypothalamic leptin receptors. Whether defects in the leptin signaling cascade play a role in the development of human obesity is a field of great actual interest that needs further research. Present evidences suggest that genetic and environmental factors influence eating behavior of people prone to obesity and that diets that are high in fat or energy dense undermine body weight regulation by promoting an overconsumption of energy relative to need.

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Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.91014.2008 ◽

2009 ◽

Vol 297 (1) ◽

pp. E211-E224 ◽

Cited By ~ 196

Author(s):

Guang Yang ◽

Leylla Badeanlou ◽

Jacek Bielawski ◽

Amanda J. Roberts ◽

Yusuf A. Hannun ◽

...

Keyword(s):

Metabolic Syndrome ◽

Body Weight ◽

Energy Expenditure ◽

Hepatic Steatosis ◽

De Novo ◽

Cytokine Signaling ◽

Weight Regulation ◽

Body Weight Regulation ◽

The Metabolic Syndrome ◽

Ceramide Synthesis

Although obesity is associated with multiple features of the metabolic syndrome (insulin resistance, leptin resistance, hepatic steatosis, chronic inflammation, etc.), the molecular changes that promote these conditions are not completely understood. Here, we tested the hypothesis that elevated ceramide biosynthesis contributes to the pathogenesis of obesity and the metabolic syndrome. Chronic treatment for 8 wk of genetically obese ( ob/ob), and, high-fat diet-induced obese (DIO) mice with myriocin, an inhibitor of de novo ceramide synthesis, decreased circulating ceramides. Decreased ceramide was associated with reduced weight, enhanced metabolism and energy expenditure, decreased hepatic steatosis, and improved glucose hemostasis via enhancement of insulin signaling in the liver and muscle. Inhibition of de novo ceramide biosynthesis decreased adipose expression of suppressor of cytokine signaling-3 (SOCS-3) and induced adipose uncoupling protein-3 (UCP3). Moreover, ceramide directly induced SOCS-3 and inhibited UCP3 mRNA in cultured adipocytes suggesting a direct role for ceramide in regulation of metabolism and energy expenditure. Inhibition of de novo ceramide synthesis had no effect on adipose tumor necrosis factor-α (TNF-α) expression but dramatically reduced adipose plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattactant protein-1 (MCP-1). This study highlights a novel role for ceramide biosynthesis in body weight regulation, energy expenditure, and the metabolic syndrome.

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Melatonin and lighting condition: Absence of long-term effects on food intake and body weight regulation in the albino rat

Physiology & Behavior ◽

10.1016/0031-9384(80)90304-2 ◽

1980 ◽

Vol 25 (6) ◽

pp. 855-857 ◽

Cited By ~ 8

Author(s):

John Dark ◽

Linda L. Rayha ◽

Ian Clark-Lane ◽

Victoria Kimler

Keyword(s):

Body Weight ◽

Food Intake ◽

Weight Regulation ◽

Body Weight Regulation ◽

Long Term Effects ◽

Albino Rat ◽

Lighting Condition

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Energy expenditure and subsequent nutrient intakes in overfed young men

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1990.259.3.r461 ◽

1990 ◽

Vol 259 (3) ◽

pp. R461-R469 ◽

Cited By ~ 12

Author(s):

S. B. Roberts ◽

V. R. Young ◽

P. Fuss ◽

M. A. Fiatarone ◽

B. Richard ◽

...

Keyword(s):

Body Weight ◽

Energy Expenditure ◽

Energy Intake ◽

Resting Metabolic Rate ◽

Young Men ◽

Resting Energy Expenditure ◽

Weight Regulation ◽

Body Weight Regulation ◽

Nutrient Intakes ◽

Normal Body Weight

We investigated the mechanisms of body weight regulation in young men of normal body weight leading unrestricted lives. Changes in total and resting energy expenditure, body composition, and subsequent voluntary nutrient intakes in response to overeating by 4,230 +/- 115 (SE) kJ/day (1,011 +/- 27 kcal/day) for 21 days were measured in seven subjects consuming a typical diet. On average, 85-90% of the excess energy intake was deposited (with 87% of this amount in fat and 13% in protein on average). There was no detectable difference between individuals in susceptibility to energy deposition. The resting metabolic rate, averaged for fasting and fed states, increased during overfeeding (mean +/- SE, 628 +/- 197 kJ/day, P less than 0.01), but at least some of this amount was obligatory expenditure associated with nutrient assimilation. No significant increase in energy expenditure for physical activity or thermoregulation resulted from overfeeding. Thus energy expenditure did not substantially adapt to increased energy intake. However, significant decreases in voluntary energy intake (1,991 +/- 824 kJ/day, P less than 0.05) and fat intake (48 +/- 11 g/day, P less than 0.01) followed overeating, indicating that adaptive changes in nutrient intakes can contribute significantly to body weight regulation after overeating.

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Long-term Effects of Early Malnutrition on Body Weight Regulation

Nutrition Reviews ◽

10.1301/nr.2004.jul.s127-s133 ◽

2004 ◽

Vol 62 (7) ◽

pp. 127-133 ◽

Cited By ~ 13

Author(s):

Ana Lydia Sawaya ◽

Paula A. Martins ◽

Luciane P. Grillo ◽

Telma T. Florêncio

Keyword(s):

Body Weight ◽

Weight Regulation ◽

Body Weight Regulation ◽

Long Term Effects

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Mice lacking PC1/3 expression in POMC-expressing cells do not develop obesity

Endocrinology ◽

10.1210/endocr/bqab055 ◽

2021 ◽

Author(s):

Manita Shakya ◽

Surbhi Gahlot ◽

Anne White ◽

C Bruce Verchere ◽

Malcolm J Low ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Energy Expenditure ◽

Weight Regulation ◽

Body Weight Regulation ◽

Obesity Risk ◽

Melanocortin System ◽

Adult Mice ◽

Pharmacological Studies ◽

The Impact

Abstract Pro-opiomelanocortin (POMC) neurons form an integral part of the central melanocortin system regulating food intake and energy expenditure. Genetic and pharmacological studies have revealed that defects in POMC synthesis, processing, and receptor signaling lead to obesity. It is well established that POMC is extensively processed by a series of enzymes, including prohormone convertases PC1/3 and PC2, and that genetic insufficiency of both PC1/3 and POMC is strongly associated with obesity risk. However, whether PC1/3-mediated POMC processing is absolutely tied to body weight regulation is not known. To investigate this question, we generated a Pomc-CreER T2; Pcsk1 lox/lox mouse model in which Pcsk1 is specifically and temporally knocked out in POMC-expressing cells of adult mice by injecting tamoxifen at eight weeks of age. We then measured the impact of Pcsk1 deletion on POMC cleavage to ACTH and α-MSH, and on body weight. In whole pituitary, POMC cleavage was significantly impacted by the loss of Pcsk1, while hypothalamic POMC-derived peptide levels remained similar in all genotypes. However, intact POMC levels were greatly elevated in Pomc-CreER T2; Pcsk1 lox/lox mice. Males expressed two-fold greater levels of pituitary PC1/3 protein than females, consistent with their increased POMC cleavage. Past studies show that mice with germline removal of PC1/3 do not develop obesity, while mice expressing mutant PC1/3 forms do develop obesity. We conclude that obesity pathways are not disrupted by PC1/3 loss solely in POMC-expressing cells, further disfavoring the idea that alterations in POMC processing underlie obesity in PCSK1 deficiency.

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