Case reportMRI detection of brown adipose tissue with low fat content in newborns with hypothermia☆
Introduction
Hypoxic–ischemic encephalopathy (HIE) is a condition in newborns in which blood flow and/or oxygen supply to the brain is interrupted or impaired, consequently increasing the risk of brain injury and neurological deficit. Risks include respiratory failure, alteration of muscle tone and reflexes, seizures, and abnormal levels of consciousness. HIE is often associated with birth asphyxia. Hypothermia therapy (HT) is one form of treatment for newborns with moderate to severe HIE. The procedure involves lowering the body core temperature by 3 °C to 4 °C below normal (36 °C–37 °C), typically for 48 to 72 hours. A cooling device is typically used in HT to maintain body temperature around 33 °C. The purpose of HT is to attenuate secondary energy failure in the patient and to reduce the ensuing incidence of neurological disability and death in the neonates [1], [2], [3], [4], [5].
In this work, we utilized water-fat MRI and its associated fat-signal fraction (FF) metric [6] to report observational findings of brown adipose tissue (BAT) with relatively low fat content (e.g. low FF) in HIE neonates after they have undergone HT. Although the framework of using FF to characterize BAT morphology was proposed and demonstrated in rodents more than a decade ago [7], the concept has seen a resurgence with corroborative results in mice [8], [9] and humans [10], [11] in recent years. One underlying premise is that BAT typically has a lower FF than triglyceride-rich white adipose tissue (WAT), and that the FF varies as a function of the tissue's metabolic activity.
BAT is implicated in non-shivering thermogenesis [12], [13] and the regulation of core body temperature. The tissue primarily consumes intracellular fat stores to generate heat via oxidative metabolism [14], [15], [16]. Thus, another underlying premise is that BAT metabolic activity can lead to the expenditure and subsequent depletion of intracellular fat, and consequently lead to a lower tissue FF. This notion has been demonstrated in a recent study, where the investigators showed a positive correlation between interscapular BAT FF values in mice and their ambient housing temperature [17]. Building on several seminal studies that have shown an increase in BAT thermogenic activity and a reduction in intracellular fat content in cold-exposed animals [18], [19], [20], [21], [22], we hypothesize in this investigation that HIE neonates undergoing 48 hours of HT will likely exhibit BAT depots with low or depleted fat stores as a response to the cold exposure. We report our water-fat MRI findings in 10 HIE cases post-HT and compare them to five non-HIE newborns.
Section snippets
Cohort
Between May 2012 and July 2013, 10 full-term HIE newborns undergoing HT at our institution were studied. In accordance with the Department of Neonatology and the Neonatal & Infant Critical Care Unit (NICCU) protocol, HT duration was set for 48 hours using a water-based temperature regulation system (Blanketrol III, Cincinnati Sub-Zero Products, Inc., Cincinnati, OH). HT was initiated upon admittance at our hospital, typically within a few hours to 1 day after birth. Gender, age, and fiber optic
Results
Fig. 2 illustrates linear correlations for intra-operator agreement, plotting the mean FF and T2* values of the two BAT depots and the WAT layer from the two analysis runs. For supraclavicular, interscapular, and subcutaneous measurements, the correlations (r2) for FF were 0.95, 0.93, and 0.96, respectively. Similarly for T2*, the r2 values were 0.93, 0.98, and 0.91, respectively. All of the correlations were p < 0.01, suggesting acceptable intra-operator performance. Fig. 3 represents the
Discussion
Using water-fat MRI data in conjunction with conventional T2w images, we have observed BAT depots with relatively low fat content in HIE newborns undergoing HT, in support of historical literature reports implicating fat-depleted brown adipocytes in hypothermia [37], [38], [39]. It is believed that even in healthy newborns, there is a natural cold exposure to ambient temperature upon birth, accompanied by an anticipated rapid loss of heat (due to their large surface-to-volume ratio) following
Acknowledgment
The authors are grateful to the following (in alphabetical order): Stefan Blüml, PhD, Julia Castro, Mercedes Landaverde, Claire McLean, MD, Lisa Villanueva, Jessica Wisnowski, PhD, Daisy Zazueta, and all of the staff in Radiology and Neonatology of Children's Hospital Los Angeles involved in this study for coordination and assistance.
References (63)
- et al.
Cooling in the real world: therapeutic hypothermia in hypoxic ischemic encephalopathy
Eur J Pediatr Neurol
(2013) - et al.
In vivo quantitative lipidic map of brown adipose tissue by chemical shift imaging at 4.7 Tesla
J Lipid Res
(1999) - et al.
Variations in T2* and fat content of murine brown and white adipose tissue by chemical-shift MRI
Magn Reson Imaging
(2012) Nonshivering thermogenesis
Brain Res Bull
(1984)- et al.
Composition of adipose tissue and marrow fat in humans by 1H NMR at 7 Tesla
J Lipid Res
(2008) - et al.
Sudden infant death syndrome (SIDS): disordered brown fat metabolism and thermogenesis
Med Hypotheses
(1994) - et al.
Subcutaneous fat necrosis
J Pediatr
(2013) - et al.
Magnetic resonance spectroscopy investigations of brown adipose tissue and isolated brown adipocytes
J Lipid Res
(1994) - et al.
Localized proton magnetic resonance spectroscopy of lipids in adipose tissue at high spatial resolution in mice in vivo
J Lipid Res
(2008) - et al.
Quantitative MR imaging of individual muscle involvement in facioscapulohumeral muscular dystrophy
Neuromuscul Disord
(2009)
Whole-body hypothermia for neonates with hypoxic–ischemic encephalopathy
N Engl J Med
Therapeutic hypothermia for hypoxic-ischaemic encephalopathy in the newborn infant
Curr Opin Neurol
Moderate hypothermia to treat perinatal asphyxial encephalopathy
N Engl J Med
Childhood outcomes after hypothermia for neonatal encephalopathy
N Engl J Med
Proton density fat-fraction: a standardized MR-based biomarker of tissue fat concentration
J Magn Reson Imaging
Comparison of brown and white adipose tissue fat fractions in ob, seipin, and Fsp27 gene knockout mice by chemical shift-selective imaging and 1H-MR spectroscopy
Am J Physiol Endocrinol Metab
Unequivocal identification of brown adipose tissue in a human infant
J Magn Reson Imaging
Evidence of two types of brown adipose tissue in humans
Nat Med
Brown fat and thermogenesis
Physiol Rev
Fuel selection in brown adipose tissue
Proc Nutr Soc
Yes, even brown fat is on fire!
J Clin Invest
Brown adipose tissue as a regulator of energy expenditure and body fat in humans
Diabetes Metab J
Measurement of interscapular brown adipose tissue of mice in differentially housed temperatures by chemical-shift-encoded MRI
J Magn Reson Imaging
Cytological responses of brown fat tissue in cold-exposed rats
J Cell Biol
Thermogenesis of brown adipose tissue in cold-acclimated rats
Am J Physiol
Brown adipose tissue and the response of new-born rabbits to cold
J Physiol
The contribution of brown adipose tissue to heat production in the new-born rabbit
J Physiol
Heat production in the new-born rabbit and the fat content of the brown adipose tissue
J Physiol
Comparison of brown and white adipose tissues in infants and children with chemical-shift-encoded water-fat MRI
J Magn Reson Imaging
Water-fat separation with IDEAL gradient-echo imaging
J Magn Reson Imaging
Dixon techniques for water and fat imaging
J Magn Reson Imaging
Cited by (34)
Opioid analgesia and temperature regulation are associated with EEG background activity and MRI outcomes in neonates with mild-to-moderate hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia
2022, European Journal of Paediatric NeurologyCitation Excerpt :However, shivering is unlikely to have the same impact on newborns compared to adults [37], as newborns depend primarily on metabolizing brown adipose tissue (BAT) to increase the rate of heat production and may only shiver when metabolic thermogenesis alone remains insufficient. Neonates with HIE who have undergone TH have shown depleted fat content in the BAT regions, reinforcing the preference for nonshivering thermogenesis to cope with hypothermia-induced stress [38]. Assuming that skin temperature increased as a result of thermoregulation, neonates who received relatively lower sedative doses may have had an increased perception of cold, which could have led to subsequent increase in endogenous heat production to combat hypothermia.
The Fat Fraction Percentage of White Adipose Tissue at various Ages in Humans: An Updated Review
2021, Journal of Clinical DensitometryCitation Excerpt :In this review, pooled means were calculated by taking the weighted mean of the study sample for each age group (12). Nineteen studies (9–11, 13–28) were included in our analysis (Table 1). Of those studies, two studies targeted neonates (10,13), one study targeted both neonates and children (9), three studies targeted children (14,16,17), one study targeted both children and adults (15), and eleven studies targeted adults (18–28).
Differentiating brown and white adipose tissues by high-resolution diffusion NMR spectroscopy
2017, Journal of Lipid ResearchCitation Excerpt :Conversely, WAT demonstrated increased strength of fat resonances compared with BAT. Earlier MRI and MR spectroscopy studies of BAT and WAT demonstrated a decrease in the fat fraction of BAT compared with WAT (15, 50–52). The various resonances of fatty acyl chains of tissue triglycerides from BAT and WAT in the spectra permit the estimation of saturation, unsaturation, and mean chain lengths (40, 52).
Identification of brown adipose tissue in an adult human using parametric data reconstructed from a 2-point Dixon magnetic resonance imaging sequence acquired simultaneously with FDG PET
2016, Journal of Clinical and Translational Endocrinology: Case ReportsCitation Excerpt :Currently, FDG PET has widespread recognition as the gold standard for BAT detection and quantification, but it necessitates the use of ionising radiation which can be a significant disadvantage in non-oncology applications. BAT with low fat content has been shown to be detectable by MRI in neonates with hypoxic-ischaemic encephalopathy undergoing hypothermia therapy [4], the speculation being that hypothermia likely promotes BAT-mediated non-shivering thermogenesis which subsequently depletes the tissue's intracellular fat stores. Reddy et al. reported the first reliable use of MRI to identify BAT in a living human adult, with histological/immunohistochemical confirmation [5].
Loss of Uncoupling Protein 1 Expression in the Subcutaneous Adipose Tissue Predicts Childhood Obesity
2023, International Journal of Molecular Sciences
- ☆
Grant support: To V.G.: R21DK090778 (National Institutes of Health/NIDDK). To H.H.: K25DK087931 (National Institutes of Health/NIDDK), Zumberge Fund, Office of the Provost, University of Southern California.