BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis

Expression of bone morphogenetic protein 4 (BMP4) in adipocytes of white adipose tissue (WAT) produces “white adipocytes” with characteristics of brown fat and leads to a reduction of adiposity and its metabolic complications. Although BMP4 is known to induce commitment of pluripotent stem cells to the adipocyte lineage by producing cells that possess the characteristics of preadipocytes, its effects on the mature white adipocyte phenotype and function were unknown. Forced expression of a BMP4 transgene in white adipocytes of mice gives rise to reduced WAT mass and white adipocyte size along with an increased number of a white adipocyte cell types with brown adipocyte characteristics comparable to those of beige or brite adipocytes. These changes correlate closely with increased energy expenditure, improved insulin sensitivity, and protection against diet-induced obesity and diabetes. Conversely, BMP4-deficient mice exhibit enlarged white adipocyte morphology and impaired insulin sensitivity. We identify peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) as the target of BMP signaling required for these brown fat-like changes in WAT. This effect of BMP4 on WAT appears to extend to human adipose tissue, because the level of expression of BMP4 in WAT correlates inversely with body mass index. These findings provide a genetic and metabolic basis for BMP4’s role in altering insulin sensitivity by affecting WAT development.     

Melatonin multiple effects on brown adipose tissue molecular machinery

Brown adipose tissue (BAT) influences energy balance through nonshivering thermogenesis, and its metabolism daily and seasonal variations are regulated by melatonin through partially known mechanisms. We evaluated the role of melatonin in BAT molecular machinery of male Control, pinealectomized (PINX), and melatonin‐treated pinealectomized (PINX/Mel) adult rats. BAT was collected either every 3 hours over 24 hours or after cold or high‐fat diet (HFD) acute exposure. HFD PINX animals presented decreased Dio2 expression, while HFD PINX/Mel animals showed increased Dio2, Ucp1, and Cidea expression. Cold‐exposed PINX rats showed decreased Dio2 and Lhs expression, and melatonin treatment augmented Adrβ3, Dio2, Ucp1, and Cidea expression. Daily profiles analyses showed altered Dio2, Lhs, Ucp1, Pgc1α, and Cidea gene and UCP1 protein expression in PINX animals, leading to altered rhythmicity under sub‐thermoneutral conditions, which was partially restored by melatonin treatment. The same was observed for mitochondrial complexes I, II, and IV protein expression and enzyme activity. Melatonin absence seems to impair BAT responses to metabolic challenges, and melatonin replacement reverses this effect, with additional increase in the expression of crucial genes, suggesting that melatonin plays an important role in several key points of the thermogenic activation pathway, influencing both the rhythmic profile of the tissue and its ability to respond to metabolic challenges, which is crucial for the organism homeostasis.     

棕色脂肪组织的形成及其作用机制

人体内脂肪组织分为棕色脂肪组织(BAT)和白色脂肪组织(WAT).它们在组织形态和生理作用上存在较大差异,BAT主要在寒冷环境或交感神经兴奋下参与产热过程,而WAT主要以甘油三酯的形式储存多余能量.通过对BAT形成和作用机制的研究发现,两种脂肪组织的起源不同,并且揭示出部分细胞因子与BAT形成及活化之间的复杂关系,从而...     

Resting energy expenditure, growth hormone indices, body composition and adipose tissue distribution in premenopausal women

OBJECTIVES: A significant growth hormone (GH) contribution to interindividual variance in energy expenditure (REE) in women can be hypothesized. The present study examines the independent association between physiological levels of GH function indices and REE. SETTING: All subjects were hospitalized in the Institute of Internal Medicine of the University of Verona. SUBJECTS: Twenty-four premenopausal overweight (BMI = 28-55 kg m-2) women aged 18-49 years. INTERVENTIONS: REE was estimated by indirect calorimetry and body composition and fat distribution by single slice computed tomography method. GH activity and GH status were determined by measuring serum levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3). RESULTS: GH indices did not show any significant correlation with REE. The relation between GH indices and REE was also examined by multiple regression analysis to account for possible confounders such as body composition, adipose tissue distribution and age. When body composition was considered, body fat and fat-free mass were the only significant predictors of REE (R2 = 0.699, P = 0.0001). The contributions of GH indices were not significant. CONCLUSIONS: Our findings do not support the hypothesis that GH in physiological conditions could be an independent determinant of REE in women with obesity.     

Non-shivering thermogenesis in brown adipose tissue and aging

The aging-induced decrease in non-shivering thermogenic capacity was prevented in the genetically CCK-A receptor deficient, diabetic obese OLETF rats, provably by an increase in the responsiveness of BAT to glucagon. The potential metabolic capacities can be sustained until aged period.     

Liraglutide decreases energy expenditure and does not affect the fat fraction of supraclavicular brown adipose tissue in patients with type 2 diabetes

Background and aimsSeveral studies have shown that glucagon-like peptide-1 (GLP-1) analogues can affect resting energy expenditure, and preclinical studies suggest that they may activate brown adipose tissue (BAT). The aim of the present study was to investigate the effect of treatment with liraglutide on energy metabolism and BAT fat fraction in patients with type 2 diabetes.Methods and resultsIn a 26-week double-blind, placebo-controlled trial, 50 patients with type 2 diabetes were randomized to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after treatment for 4, 12 and 26 weeks, we assessed resting energy expenditure (REE) by indirect calorimetry. Furthermore, at baseline and after 26 weeks, we determined the fat fraction in the supraclavicular BAT depot using chemical-shift water-fat MRI at 3T. Liraglutide reduced REE after 4 weeks, which persisted after 12 weeks and tended to be present after 26 weeks (week 26 vs baseline: liraglutide −52 ± 128 kcal/day; P = 0.071, placebo +44 ± 144 kcal/day; P = 0.153, between group P = 0.057). Treatment with liraglutide for 26 weeks did not decrease the fat fraction in supraclavicular BAT (−0.4 ± 1.7%; P = 0.447) compared to placebo (−0.4 ± 1.4%; P = 0.420; between group P = 0.911).ConclusionTreatment with liraglutide decreases REE in the first 12 weeks and tends to decrease this after 26 weeks without affecting the fat fraction in the supraclavicular BAT depot. These findings suggest reduction in energy intake rather than an increase in REE to contribute to the liraglutide-induced weight loss.Trial registry numberNCT01761318.     

Impaired metabolic response to nerve stimulation in brown adipose tissue of hypothyroid rats

In brown adipose tissue of the rat, chemically or surgically induced hypothyroidism caused the following effects. A large decrease of the magnitude of the metabolic response to electrical nerve stimulation. The deactivation half-time of the response was reduced to 70% of the control value, with no change in catechol O-methyltransferase activity. Pre-incubation of tissues with norepinephrine, 10(-5) M, increased the response to subsequent nerve stimulation almost to that of the controls. The catecholamine analogue dose-response curves were shifted to the right. The shift was very pronounced for isoproterenol (K50 426 nM versus 2 nM), somewhat less marked for norepinephrine (7373 nM versus 194) and very slight for phenylephrine (2803 nM versus 1649); there was almost no change in Emax values. An increase of octanoate oxidative capacity. A decrease of the capacity of the stereoselective binding of (-)-[3H]dihydroalprenolol of the high-affinity (Kd 2.0 nM) sites to a fourth of the control value and an increase by a factor of 2.9 of the Kd of the low-affinity binding sites. This decrease of binding to the beta-receptors was not sufficient quantitatively to explain the decrease in the metabolic response, suggesting the existence of an additional defective reaction which could occur between the binding to the beta-receptors and the activation of the triglyceride lipase. These results show that the sharp decrease of the metabolic response of brown adipose tissue to nerve stimulation has multiple causes. The findings are discussed in the context of the drastic decrease of cold resistance in hypothyroid rats.     

The role of brown adipose tissue in human obesity

It is widely accepted that newborn humans are provided with brown adipose tissue (BAT) and that adult humans lack, or have only a small amount, of it. Therefore the physiological role of BAT in humans is debated. It is quite clear that BAT in rodents has an important role in the prevention and therapy of obesity and diabetes and specific drugs can induce BAT development in adult animals. New concepts regarding the biology of adipose tissues in mammals have been developed during the last years leading to the hope for the development of BAT in human adults as a new challenge for the treatment of obesity and related diseases. These new concepts are basic to understanding the above-proposed therapeutic strategy and are the concept of the adipose organ and the concept of transdifferentiation. In this paper these new concepts will be explained together with a review of available scientific data on human BAT.     

Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity

A worldwide increase in the incidence of obesity indicates the unsuccessful battle against this disorder. Obesity and the associated health problems urgently require effective strategies of treatment. The new discovery that a substantial amount of functional brown adipose tissue (BAT) is retained in adult humans provides a potential target for treatment of human obesity. BAT is active metabolically and disposes of extra energy via generation of heat through uncoupling oxidative phosphorylation in mitochondria. The physiology of BAT is readily regulated by melatonin, which not only increases recruitment of brown adipocytes but also elevates their metabolic activity in mammals. It is speculated that the hypertrophic effect and functional activation of BAT induced by melatonin may likely apply to the human. Thus, melatonin, a naturally occurring substance with no reported toxicity, may serve as a novel approach for treatment of obesity. Conversely, because of the availability of artificial light sources, excessive light exposure after darkness onset in modern societies should be considered a potential contributory factor to human obesity as light at night dramatically reduces endogenous melatonin production. In the current article, the potential associations of melatonin, BAT, obesity and the medical implications are discussed.     

From the Cover: Prolonged daily light exposure increases body fat mass through attenuation of brown adipose tissue activity

Disruption of circadian rhythmicity is associated with obesity and related disorders, including type 2 diabetes and cardiovascular disease. Specifically, prolonged artificial light exposure associates with obesity in humans, although the underlying mechanism is unclear. Here, we report that increasing the daily hours of light exposure increases body adiposity through attenuation of brown adipose tissue (BAT) activity, a major contributor of energy expenditure. Mice exposed to a prolonged day length of 16- and 24-h light, compared with regular 12-h light, showed increased adiposity without affecting food intake or locomotor activity. Mechanistically, we demonstrated that prolonged day length decreases sympathetic input into BAT and reduces β3-adrenergic intracellular signaling. Concomitantly, prolonging day length decreased the uptake of fatty acids from triglyceride-rich lipoproteins, as well as of glucose from plasma selectively by BAT. We conclude that impaired BAT activity is an important mediator in the association between disturbed circadian rhythm and adiposity, and anticipate that activation of BAT may overcome the adverse metabolic consequences of disturbed circadian rhythmicity.Modern world society is subjected to disturbances of circadian rhythms by shift work, sleep deprivation, and environmental light pollution. Importantly, the increasing prevalence of obesity is associated with a disrupted sleep-wake pattern in humans (1) and coincides with the availability of artificial light (2, 3). Additionally, a recent study revealed a relationship between exposure to light at night and obesity in a cross-sectional analysis of over 100,000 women (4). Light input is the most important cue for generation of circadian (∼24 h) rhythms by the master clock. Both in rodents and humans the master clock is situated in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is responsible for synchronization of peripheral clocks throughout the body, which is mediated by endocrine and neuronal signals (5). A causal role for a disturbed circadian rhythm in the development of obesity has been demonstrated by animal studies. Mice with genetically dysfunctional clock genes develop obesity and insulin resistance (6–9). Moreover, specific ablation of the SCN induces acute weight gain (10). These results indicate a crucial role for the SCN in the regulation of adiposity.Interestingly, we previously showed that prolonged light exposure only is sufficient to enhance weight gain in mice. Constant light disrupts the central circadian clock, evidenced by an immediate reduction in the circadian amplitude of SCN electrical activity. Moreover, constant light induces body weight gain and insulin resistance, even faster than high-fat diet, which was not caused by increased food intake or reduced locomotor activity (11). Therefore, disruption of the central biological clock likely induces weight gain by decreasing energy expenditure.Recently, it has been recognized that brown adipose tissue (BAT) importantly contributes to energy expenditure. BAT combusts high amounts of triglycerides (TG) into heat, a process called thermogenesis that is mediated by uncoupling protein 1 (UCP1). Interestingly, SCN neurons project onto BAT and injection of glutamate into the SCN increases BAT thermogenesis in rats (12, 13). This finding indicates that BAT may mediate the association between circadian rhythmicity and energy expenditure. Therefore, the aim of this study was to shed light on the association between prolonged light exposure and obesity in humans by investigating the effect of day length on BAT activity in mice in relation to body fat gain, independent of ambient temperature. We demonstrate that daily light exposure negatively associates with the uptake of TG-derived fatty acids and glucose from plasma by BAT, pointing to decreased activity of the tissue. Furthermore, we show that increasing daily light exposure decreases BAT activity through reduced sympathetic stimulation.