scholarly journals Opportunities and challenges in the therapeutic activation of human energy expenditure and thermogenesis to manage obesity

2019 ◽  
Vol 295 (7) ◽  
pp. 1926-1942 ◽  
Author(s):  
Kong Y. Chen ◽  
Robert J. Brychta ◽  
Zahraa Abdul Sater ◽  
Thomas M. Cassimatis ◽  
Cheryl Cero ◽  
...  

The current obesity pandemic results from a physiological imbalance in which energy intake chronically exceeds energy expenditure (EE), and prevention and treatment strategies remain generally ineffective. Approaches designed to increase EE have been informed by decades of experiments in rodent models designed to stimulate adaptive thermogenesis, a long-term increase in metabolism, primarily induced by chronic cold exposure. At the cellular level, thermogenesis is achieved through increased rates of futile cycling, which are observed in several systems, most notably the regulated uncoupling of oxidative phosphorylation from ATP generation by uncoupling protein 1, a tissue-specific protein present in mitochondria of brown adipose tissue (BAT). Physiological activation of BAT and other organ thermogenesis occurs through β-adrenergic receptors (AR), and considerable effort over the past 5 decades has been directed toward developing AR agonists capable of safely achieving a net negative energy balance while avoiding unwanted cardiovascular side effects. Recent discoveries of other BAT futile cycles based on creatine and succinate have provided additional targets. Complicating the current and developing pharmacological-, cold-, and exercise-based methods to increase EE is the emerging evidence for strong physiological drives toward restoring lost weight over the long term. Future studies will need to address technical challenges such as how to accurately measure individual tissue thermogenesis in humans; how to safely activate BAT and other organ thermogenesis; and how to sustain a negative energy balance over many years of treatment.

2021 ◽  
Vol 22 (6) ◽  
pp. 2827
Author(s):  
Vicente Barrios ◽  
Laura M. Frago ◽  
Sandra Canelles ◽  
Santiago Guerra-Cantera ◽  
Eduardo Arilla-Ferreiro ◽  
...  

The growth hormone (GH)/insulin-like growth factor I (IGF-I) axis is involved in metabolic control. Malnutrition reduces IGF-I and modifies the thermogenic capacity of brown adipose tissue (BAT). Leptin has effects on the GH/IGF-I axis and the function of BAT, but its interaction with IGF-I and the mechanisms involved in the regulation of thermogenesis remains unknown. We studied the GH/IGF-I axis and activation of IGF-I-related signaling and metabolism related to BAT thermogenesis in chronic central leptin infused (L), pair-fed (PF), and control rats. Hypothalamic somatostatin mRNA levels were increased in PF and decreased in L, while pituitary GH mRNA was reduced in PF. Serum GH and IGF-I concentrations were decreased only in PF. In BAT, the association between suppressor of cytokine signaling 3 and the IGF-I receptor was reduced, and phosphorylation of the IGF-I receptor increased in the L group. Phosphorylation of Akt and cyclic AMP response element binding protein and glucose transporter 4 mRNA levels were increased in L and mRNA levels of uncoupling protein-1 (UCP-1) and enzymes involved in lipid anabolism reduced in PF. These results suggest that modifications in UCP-1 in BAT and changes in the GH/IGF-I axis induced by negative energy balance are dependent upon leptin levels.


2021 ◽  
Author(s):  
Patrick Mullie ◽  
Pieter Maes ◽  
Laurens van Veelen ◽  
Damien Van Tiggelen ◽  
Peter Clarys

ABSTRACT Introduction Adequate energy supply is a prerequisite for optimal performances and recovery. The aims of the present study were to estimate energy balance and energy availability during a selection course for Belgian paratroopers. Methods Energy expenditure by physical activity was measured with accelerometer (ActiGraph GT3X+, ActiGraph LLC, Pensacola, FL, USA) and rest metabolic rate in Cal.d−1 with Tinsley et al.’s equation based on fat-free mass = 25.9 × fat-free mass in kg + 284. Participants had only access to the French individual combat rations of 3,600 Cal.d−1, and body fat mass was measured with quadripolar impedance (Omron BF508, Omron, Osaka, Japan). Energy availability was calculated by the formula: ([energy intake in foods and beverages] − [energy expenditure physical activity])/kg FFM−1.d−1, with FFM = fat-free mass. Results Mean (SD) age of the 35 participants was 25.1 (4.18) years, and mean (SD) percentage fat mass was 12.0% (3.82). Mean (SD) total energy expenditure, i.e., the sum of rest metabolic rate, dietary-induced thermogenesis, and physical activity, was 5,262 Cal.d−1 (621.2), with percentile 25 at 4,791 Cal.d−1 and percentile 75 at 5,647 Cal.d−1, a difference of 856 Cal.d−1. Mean daily energy intake was 3,600 Cal.d−1, giving a negative energy balance of 1,662 (621.2) Cal.d−1. Mean energy availability was 9.3 Cal.kg FFM−1.d−1. Eleven of the 35 participants performed with a negative energy balance of 2,000 Cal.d−1, and only five participants out of 35 participants performed at a less than 1,000 Cal.d−1 negative energy balance level. Conclusions Energy intake is not optimal as indicated by the negative energy balance and the low energy availability, which means that the participants to this selection course had to perform in suboptimal conditions.


1998 ◽  
Vol 10 (1) ◽  
pp. 65 ◽  
Author(s):  
Stephen J. Judd

Animal reproduction is impaired when intake of energy is so restricted that activities essential to life are threatened; this is seen as a homeostatic adjustment that restricts wasteful energy expenditure. Fasting or exercising to a degree requiring considerable energy expenditure has major effects on the hypothalamus, including activation of corticotrophin-releasing factor (CRF) neurons, suppression of thyrotrophin-releasing hormone synthesis, and increased growth hormone secretion; these are associated with increased concentrations of hypothalamic neuropeptide Y mRNA and are corrected by administration of leptin, an adipose-tissue protein with a tertiary structure similar to the cytokine interleukin-2. This response to fasting results from a disordered pattern of activity in the gonadotrophin-releasing hormone (GnRH) pacemaker, characterized by reduced luteinizing hormone pulsatility, particularly during daytime. Animal studies have suggested that the response depends on an intact afferent vagal system from the stomach and the presence of oestrogen. Noradrenergic neurons forming the A2 group increase the activity of CRF neurons that, in turn, inhibit GnRH pulsatility. Reproductive impairment due to fasting is reversed by leptin, and abnormalities of leptin are described in individuals who fast or who develop exercise-induced amenorrhoea. This paper discusses these changes induced by negative energy balance and speculates on the involvement of leptin as a contributor to these abnormalities.


2020 ◽  
Vol 8 (4_suppl3) ◽  
pp. 2325967120S0020
Author(s):  
Julie A. Young ◽  
Jessica Napolitano ◽  
Mitchell J. Rauh ◽  
Jeanne Nichols ◽  
Anastasia N. Fischer

BACKGROUND: Prior studies have shown that vital signs such as heart rate, blood pressure and body temperature are depressed in patients with an eating disorder who have experienced a negative energy balance for a significant amount of time. More recently, a negative energy balance has been the focus of Relative Energy Deficiency in Sport (RED-S), which links energy availability to the health of multiple body systems in adults in as little as 5 days with a negative energy balance. High rates of disordered eating patterns have been reported in high school athletes. As adolescents grow, the consequences of a negative energy balance can be significant and potentially irreversible. Thus, vital signs may help clinicians quickly evaluate a patient’s energy status or highlight them for further evaluation. PURPOSE: The purpose of this study was to examine energy balance and vital signs in a cohort of adolescents who were seen by a sports dietitian to gain weight or optimize sports performance. METHODS: We evaluated 240 subjects, 83% female, average age 15.0±2.3 years. Heart rate and blood pressure were measured with a dynamometer in a seated position. Body temperature was measured orally. Height and weight were recorded. BMI was then calculated and evaluated by percentile. Energy intake was assessed using a 3-day food recall log. Energy expenditure was calculated using Harris Benedict Equation and combined with estimated exercise energy expenditure. Energy balance was estimated as energy intake minus energy expenditure. RESULTS: Average age was 15.03±2.71. 85% were female. 30% were below the 15th percentile for BMI. There were no differences in BMI percentiles between males and females (p=0.99). The average heart rate was 71.62±13.4 bpm and 19% were below the 10th percentile for heart rate. Average systolic blood pressure was 110±11 mm Hg and average diastolic blood pressure was 62±7 mmHg. Average temperature was 98.1±.4 degrees F. 88%were in a negative energy balance with an average energy deficit of 552±511 calories. There were no statistically significant differences in energy balance between males and females (p=0.08). CONCLUSIONS: A disproportional number of children with low BMI and heart rate percentiles was observed, which may indicate a long-standing energy deficiency. We also found a high proportion of adolescents who experienced a standalone negative energy balance itself or vital signs consistent with a negative energy balance. Additional studies are needed to study the relationships between energy deficit magnitude and duration in adolescents and children.


Metabolism ◽  
1999 ◽  
Vol 48 (9) ◽  
pp. 1120-1127 ◽  
Author(s):  
Janet Pritchard ◽  
Jean-Pierre Després ◽  
Jacques Gagnon ◽  
Adnré Tchernof ◽  
Adnré Nadeau ◽  
...  

PLoS ONE ◽  
2013 ◽  
Vol 8 (7) ◽  
pp. e67786 ◽  
Author(s):  
Pilou L. H. R. Janssens ◽  
Rick Hursel ◽  
Eveline A. P. Martens ◽  
Margriet S. Westerterp-Plantenga

1999 ◽  
Vol 276 (6) ◽  
pp. R1739-R1748 ◽  
Author(s):  
T. P. Stein ◽  
M. J. Leskiw ◽  
M. D. Schluter ◽  
R. W. Hoyt ◽  
H. W. Lane ◽  
...  

The objectives of this study were as follows: 1) to measure human energy expenditure (EE) during spaceflight on a shuttle mission by using the doubly labeled water (DLW) method; 2) to determine whether the astronauts were in negative energy balance during spaceflight; 3) to use the comparison of change in body fat as measured by the intake DLW EE,18O dilution, and dual energy X-ray absorptiometry (DEXA) to validate the DLW method for spaceflight; and 4) to compare EE during spaceflight against that found with bed rest. Two experiments were conducted: a flight experiment ( n = 4) on the 16-day 1996 life and microgravity sciences shuttle mission and a 6° head-down tilt bed rest study with controlled dietary intake ( n = 8). The bed rest study was designed to simulate the flight experiment and included exercise. Two EE determinations were done before flight (bed rest), during flight (bed rest), and after flight (recovery). Energy intake and N balance were monitored for the entire period. Results were that body weight, water, fat, and energy balance were unchanged with bed rest. For the flight experiment, decreases in weight (2.6 ± 0.4 kg, P < 0.05) and N retention (−2.37 ± 0.45 g N/day, P < 0.05) were found. Dietary intake for the four astronauts was reduced in flight (3,025 ± 180 vs. 1,943 ± 179 kcal/day, P < 0.05). EE in flight was 3,320 ± 155 kcal/day, resulting in a negative energy balance of 1,355 ± 80 kcal/day (−15.7 ± 1.0 kcal ⋅ kg−1 ⋅ day−1, P < 0.05). This corresponded to a loss of 2.1 ± 0.4 kg body fat, which was within experimental error of the fat loss determined by18O dilution (−1.4 ± 0.5 kg) and DEXA (−2.4 ± 0.4 kg). All three methods showed no change in body fat with bed rest. In conclusion, 1) the DLW method for measuring EE during spaceflight is valid, 2) the astronauts were in severe negative energy balance and oxidized body fat, and 3) in-flight energy (E) requirements can be predicted from the equation: E = 1.40 × resting metabolic rate + exercise.


1995 ◽  
Vol 73 (2) ◽  
pp. 323-334 ◽  
Author(s):  
K. Klipstein-Grobusch ◽  
J. J. Reilly ◽  
J. Potter ◽  
C. A. Edwards ◽  
M. A. Roberts

Studies on hospitalized elderly subjects have demonstrated that negative energy balance is common during hospitalization, but have concentrated primarily on long-stay and psychogeriatric patients. There is little information on energy balance in elderly patients admitted with acute illness from the community, despite the importance of this patient group and the presence of a number of factors likely to predispose such patients to negative energy balance. In the present study energy balance was quantified in twenty patients (eight males, mean age 82 (SD 05) years; twelve females, mean age 84 (SD 6) years) admitted from the community with acute illness, and predicted basal metabolic rate (BMR) was compared with measured resting metabolic rate (RMR). Most patients were in negative energy balance during hospitalization, and median measured energy intake (El):measured RMR ratio was 1·0 (range 0·7–1·8). The mean difference between measured El and estimated total energy expenditure was −1·3 MJ/d (range -3·4 to +2·5 MJ/d). Estimated total energy expenditure exceeded measured El in fifteen of the patients and there was a significant decline in mid-arm muscle circumference (paired t, P < 0·05) during hospitalization. We conclude that moderate negative energy balance is common in this patient group, and that these patients are at risk of undernutrition during their hospital stay.


2021 ◽  
Vol 22 (10) ◽  
pp. 5365
Author(s):  
Antonio J. López-Gambero ◽  
Cristina Rosell-Valle ◽  
Dina Medina-Vera ◽  
Juan Antonio Navarro ◽  
Antonio Vargas ◽  
...  

Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer’s disease (AD). Late AD is associated with amyloid (Aβ) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg5xFAD/5xFAD), heterozygous (Tg5xFAD/-), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aβ plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg5xFAD/- and Tg5xFAD/5xFAD mice and increased expression of IL-1β in Tg5xFAD/5xFAD mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg5xFAD/- and Tg5xFAD/5xFAD mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development.


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