Ken K. Y. Ho

A critical appraisal of the prevalence and metabolic significance of brown adipose tissue in adult humans

Brown adipose tissue (BAT) plays a major role in energy homeostasis in animals. Detection of BAT using positron emission tomography (PET)-CT in humans has challenged the view that BAT disappears after infancy. Several recent studies, based on analysis of single scans, have reported a low prevalence of only 5-10% in humans, casting doubt on its significance. We undertook a critical analysis of the sensitivity, reproducibility, and accuracy of PET-CT to deduce the prevalence of BAT and factors associated with its detection in adult humans. In a retrospective evaluation of PET-CT, using [18F]fluorodeoxyglucose, performed in 2,934 patients, BAT was identified in 250 patients, yielding an apparent prevalence of 8.5%. Among those patients with BAT, 145 were scanned more than once. The frequency of another scan being positive increased from 8 to 65% for one to more than four additional studies. The average probability of obtaining another positive scan among patients with BAT is 13%, from which the prevalence of BAT is estimated at 64%. BAT was more commonly detected in women, in younger (36 ± 1 vs. 52 ± 1 years, P < 0.001) and leaner (20.1 ± 0.9 vs. 24.9 ± 0.9 kg/m2, P < 0.01) individuals. Fasting glucose was lower in those with BAT than those without (4.9 ± 0.1 vs. 5.5 ± 0.1 mmol/l, P < 0.01). Among patients scanned more than once, BAT was detected when body weight and fasting glucose were lower (54.9 ± 0.5 vs. 58.2 ± 0.8 kg, P < 0.001 and 4.9 ± 0.3 vs. 5.5 ± 0.3 mmol/l, P = 0.03). We conclude that BAT is present in the majority of adult humans. Presence of BAT correlates negatively with body mass index and glucose concentration. BAT may play an important role in energy homeostasis in adults.

Expert consensus document: A consensus on the medical treatment of acromegaly

In March 2013, the Acromegaly Consensus Group met to revise and update guidelines for the medical treatment of acromegaly. The meeting comprised experts skilled in the medical management of acromegaly. The group considered treatment goals covering biochemical, clinical and tumour volume outcomes, and the place in guidelines of somatostatin receptor ligands, growth hormone receptor antagonists and dopamine agonists, and alternative modalities for treatment including combination therapy and novel treatments. This document represents the conclusions of the workshop consensus.

Effects of different oral oestrogen formulations on insulin-like growth factor-I, growth hormone and growth hormone binding protein in post-menopausal women.

OBJECTIVE Insulin like growth factor‐I (IGF‐I) levels in post‐menopausal women are reduced by oral administration of the synthetic oestrogen ethinyl oestradiol but increased by transdermal delivery of 17 β‐oestradiol. Since these oestrogen types are different, the aim of this study was to clarify whether reduction in IGF‐I is a specific effect of ethinyl oestradiol or common to other oral oestrogen formulations.

Modulation of growth hormone action by sex steroids

Growth hormone (GH) is a major regulator of growth, somatic development and body composition. Sex steroids can act centrally by regulating GH secretion and peripherally modulating GH responsiveness. This review addresses data of potential clinical relevance on how sex steroids modulate GH secretion and action, aiming to increase the understanding of sex steroid/GH interactions and leading to improved management of patients. Sex steroids regulate GH secretion directly as well as indirectly through IGF‐I modulation. Testosterone stimulates GH secretion centrally, an effect dependent on prior aromatization to oestrogen. Oestrogen stimulates GH secretion indirectly by reducing IGF‐I feedback inhibition. Whether oestrogen stimulates GH secretion centrally in females is unresolved.

Brown Adipose Tissue in Adult Humans: A Metabolic Renaissance

Brown adipose tissue (BAT) plays a key role in energy homeostasis and thermogenesis in animals, conferring protection against diet-induced obesity and hypothermia through the action of uncoupling protein 1 (UCP1). Recent metabolic imaging studies using positron emission tomography computerized tomography (PET-CT) scanning have serendipitously revealed significant depots of BAT in the cervical-supraclavicular regions, demonstrating persistence of BAT beyond infancy. Subsequent cold-stimulated PET-CT studies and direct histological examination of adipose tissues have demonstrated that BAT is highly prevalent in adult humans. BAT activity correlates positively with increment of energy expenditure during cold exposure and negatively with age, body mass index, and fasting glycemia, suggesting regulatory links between BAT, cold-induced thermogenesis, and energy metabolism. Human BAT tissue biopsies express UCP1 and harbor inducible precursors that differentiate into UCP1-expressing adipocytes in vitro. These recent discoveries represent a metabolic renaissance for human adipose biology, overturning previous belief that BAT had no relevance in adult humans. They also have implications for the understanding of the pathogenesis and treatment of obesity and its metabolic sequelae.

Characterization of 24‐hour growth hormone secretion in acromegaly: implications for diagnosis and therapy

OBJECTIVE Early studies of acromegaly undertaken before the general availability of insulin‐like growth factor I (IGF‐I) assays have used arbitrary and varying growth hormone (GH) threshold levels for diagnosing and assessing outcome of treatment for this disease. We have undertaken a detailed study of GH secretion and its relationship to IGF‐I levels to assess the usefulness of GH and IGF‐I measurements in the assessment of acromegaly.

High prevalence of brown adipose tissue in adult humans

CONTEXT Positron emission tomography (PET)-computed tomography (CT) has identified metabolically active supraclavicular fat in adult humans based on uptake of labeled glucose and confirmed to be brown adipose tissue (BAT) histologically. However, PET-CT has estimated a prevalence of BAT as low as 5% in adult humans, casting doubt on its significance. The true prevalence of BAT is unknown because of the suboptimal sensitivity of standard PET-CT. OBJECTIVE The objective of the study was to determine whether BAT is present in PET-negative supraclavicular fat. DESIGN This was a prospective cohort study. SETTING The study was conducted at a tertiary referral hospital. PATIENTS Seventeen patients who underwent preoperative PET-CT for staging of head and neck malignancy participated in the study. MAIN OUTCOME The main outcome was signature BAT gene transcripts and protein in biopsies of supraclavicular fat with sc fat as negative control. RESULTS PET-CT was positive in three and negative in 14 patients. PET-positive fat harbored multilobulated lipid droplets and stained strongly for uncoupling protein 1 (UCP1). These features are absent in sc fat. By contrast, PET-negative fat contained a predominance of cells with unilobulated lipid droplets, with scattered cells containing multilobulated lipid droplets and variable UCP1 staining. Molecular analyses of fat biopsies showed lower but clear expression of UCP1, NDUFS3 (NADH dehydrogenase (ubiquinone) iron-sulfur protein 3), β₃-adrenoceptor, and PRDM16 (PR domain containing 16) transcripts. CONCLUSIONS BAT is present in supraclavicular fat, regardless of PET status. BAT is highly prevalent in adult humans, and its abundance determines PET status.

The Effects of Growth Hormone on Body Composition and Physical Performance in Recreational Athletes: A Randomized Trial

BACKGROUND Growth hormone is widely abused by athletes, frequently with androgenic steroids. Its effects on performance are unclear. OBJECTIVE To determine the effect of growth hormone alone or with testosterone on body composition and measures of performance. DESIGN Randomized, placebo-controlled, blinded study of 8 weeks of treatment followed by a 6-week washout period. Randomization was computer-generated with concealed allocation. (Australian-New Zealand Clinical Trials Registry registration number: ACTRN012605000508673) SETTING Clinical research facility in Sydney, Australia. PARTICIPANTS 96 recreationally trained athletes (63 men and 33 women) with a mean age of 27.9 years (SD, 5.7). INTERVENTION Men were randomly assigned to receive placebo, growth hormone (2 mg/d subcutaneously), testosterone (250 mg/wk intramuscularly), or combined treatments. Women were randomly assigned to receive either placebo or growth hormone (2 mg/d). MEASUREMENTS Body composition variables (fat mass, lean body mass, extracellular water mass, and body cell mass) and physical performance variables (endurance [maximum oxygen consumption], strength [dead lift], power [jump height], and sprint capacity [Wingate value]). RESULTS Body cell mass was correlated with all measures of performance at baseline. Growth hormone significantly reduced fat mass, increased lean body mass through an increase in extracellular water, and increased body cell mass in men when coadministered with testosterone. Growth hormone significantly increased sprint capacity, by 0.71 kJ (95% CI, 0.1 to 1.3 kJ; relative increase, 3.9% [CI, 0.0% to 7.7%]) in men and women combined and by 1.7 kJ (CI, 0.5 to 3.0 kJ; relative increase, 8.3% [CI, 3.0% to 13.6%]) when coadministered with testosterone to men; other performance measures did not significantly change. The increase in sprint capacity was not maintained 6 weeks after discontinuation of the drug. LIMITATIONS Growth hormone dosage may have been lower than that used covertly by competitive athletes. The athletic significance of the observed improvements in sprint capacity is unclear, and the study was too small to draw conclusions about safety. CONCLUSION Growth hormone supplementation influenced body composition and increased sprint capacity when administered alone and in combination with testosterone. PRIMARY FUNDING SOURCE The World Anti-Doping Agency.

Aging and Growth Hormone

Detailed studies of the ontogeny of growth hormone (GH) secretion have shown unequivocally that GH is produced throughout life but secretion declines progressively to about 20% of that in puberty. These changes are accounted for in part by changes in central neuro-endocrine function, nutritional factors and by changes in sex steroid milieu. Mean 24-hour GH concentrations in the normal elderly are frequently below the limit of assay detectability where values are indistinguishable from matched adults with organic GH deficiency. The notion that diminished GH action may account for the undesirable changes in body composition and function in the elderly is supported by beneficial findings of GH treatment in GH-deficient adults. Preliminary results of GH treatment in the normal elderly suggest beneficial effects on body composition but a high incidence of side-effects. Questions addressing cost, benefit, dosage, safety and tolerance need to be critically addressed before GH can be considered for use in the aging.

Inducible Brown Adipogenesis of Supraclavicular Fat in Adult Humans

Brown adipose tissue (BAT) plays key roles in thermogenesis and energy homeostasis in rodents. Metabolic imaging using positron emission tomography (PET)-computer tomography has identified significant depots of BAT in the supraclavicular fossa of adult humans. Whether supraclavicular fat contains precursor brown adipocytes is unknown. The aim of the present study was to determine the adipogenic potential of precursor cells in human supraclavicular fat. We obtained fat biopsies from the supraclavicular fossa of six individuals, as guided by PET-computer tomography, with paired sc fat biopsies as negative controls. Each piece of fat tissue was divided and processed for histology, gene analysis, and primary culture. Cells were examined for morphological changes in culture and harvested for RNA and protein upon full differentiation for analysis of UCP1 level. Histological/molecular analysis of supraclavicular fat revealed higher abundance of BAT in PET-positive than PET-negative individuals. In all subjects, fibroblast-like cells isolated from supraclavicular fat differentiated in vitro and uniformly into adipocytes containing multilobulated lipid droplets, expressing high level of UCP1. The total duration required from inoculation to emergence of fibroblast-like cells was 32-34 and 40-42 d for PET-positive- and PET-negative-derived samples, respectively, whereas the time required to achieve full differentiation was 7 d, regardless of PET status. Precursor cells from sc fat failed to proliferate or express UCP1. In summary, preadipocytes isolated from supraclavicular fat are capable of differentiating into brown adipocytes in vitro, regardless of PET status. This study provides the first evidence of inducible brown adipogenesis in the supraclavicular region in adult humans.