Selective Glucocorticoid Receptor Antagonist CORT125281 Activates Brown Adipose Tissue and Alters Lipid Distribution in Male Mice

Electrical stimulation of the ventromedial hypothalamic area in rats caused a significant but transient increase in interscapular brown adipose tissue temperature. This response was markedly reduced by cimetidine, a histamine H2-receptor antagonist, but not by pyrilamine, an H1-receptor antagonist. Histamine is present in substantial amounts within mast cells in brown adipose tissue as injections of compound 48/80, which cause degranulation of connective tissue mast cells, reduced the tissue histamine content by > 85%. In contrast, histamine content in brown adipose tissue was not affected by loss of sympathetic neural input (with 6-hydroxydopamine) or sensory neural input (with capsaicin). Neither cimetidine nor histamine had any effect on basal and norepinephrine-stimulated rates of O2 consumption by isolated brown adipocytes. These results indicate that histamine released from mast cells acting on H2-receptors may play an important but indirect role in the thermogenic response of brown adipose tissue to stimulation of the ventromedial hypothalamic area.

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Specific knockout of p85α in brown adipose tissue induces resistance to high-fat diet–induced obesity and its metabolic complications in male mice

Molecular Metabolism ◽

10.1016/j.molmet.2019.10.010 ◽

2020 ◽

Vol 31 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Almudena Gomez-Hernandez ◽

Andrea R. Lopez-Pastor ◽

Carlota Rubio-Longas ◽

Patrik Majewski ◽

Nuria Beneit ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

High Fat Diet ◽

Male Mice ◽

High Fat ◽

Metabolic Complications ◽

Diet Induced Obesity ◽

Brown Adipose

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Brown adipose tissue thermogenesis, torpor, and obesity of glutamate-treated mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1986.251.4.e407 ◽

1986 ◽

Vol 251 (4) ◽

pp. E407-E415 ◽

Cited By ~ 9

Author(s):

K. Tokuyama ◽

J. Himms-Hagen

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Normal Male ◽

Obese Mouse ◽

Metabolic Efficiency ◽

Obese Mice ◽

Male Mice ◽

Corticosterone Concentration ◽

Female Mice ◽

Brown Adipose

Mice treated with glutamate in the neonatal period are known to develop into stunted obese adults, despite hypophagia. Our objective was to find out whether brown adipose tissue (BAT) thermogenic function might be abnormal in the glutamate-obese mouse. At 10 wk of age, group-housed glutamate-obese mice exhibited nocturnal and early diurnal torpor, i.e., they thermoregulated at a lower than normal body temperature. When exposed to 4 degrees C, they died in hypothermia within 24 h. They could adapt to living at 14 degrees C for up to 1 wk but failed to adjust their food intake sufficiently to maintain their body weight. Their fat stores were, nevertheless, conserved. BAT was present in increased amounts in glutamate-obese mice. Its thermogenic activity (as assessed by the level of mitochondrial GDP binding) was normal (male mice) or reduced (female mice). A normal thermogenic responsiveness of BAT to cold occurred. The thermogenic response of BAT to a cafeteria diet was normal (male mice) or reduced (female mice). Serum corticosterone concentration was increased in both male and female glutamate-treated mice particularly in the cold. We conclude that the high metabolic efficiency and obesity of the glutamate-obese mouse are principally a consequence of its maintenance of a hypothermic torpid state for more than 50% of the time. An additional deficit in energy expenditure in female, but not male, glutamate-obese mice is associated with suppressed responsiveness of the thermogenic function of BAT to diet and may account for the greater degree of obesity in female than in male glutamate-treated mice.

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Dietary low ratio of n‐6/n‐3 polyunsaturated fatty acids improve type 2 diabetes mellitus via activating brown adipose tissue in male mice

Journal of Food Science ◽

10.1111/1750-3841.15645 ◽

2021 ◽

Author(s):

Hao Yue ◽

Wei Liu ◽

Wenlong Zhang ◽

Min Jia ◽

Fenghong Huang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Fatty Acids ◽

Type 2 Diabetes Mellitus ◽

Adipose Tissue ◽

Polyunsaturated Fatty Acids ◽

Brown Adipose Tissue ◽

Male Mice ◽

Brown Adipose

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Endogenous activation of spinal 5-hydroxytryptamine (5-HT) receptors contributes to the thermoregulatory activation of brown adipose tissue

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00614.2009 ◽

2010 ◽

Vol 298 (3) ◽

pp. R776-R783 ◽

Cited By ~ 34

Author(s):

Christopher J. Madden ◽

Shaun F. Morrison

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Receptor Antagonist ◽

Pseudorabies Virus ◽

Area Under The Curve ◽

Whole Body ◽

Baseline Activity ◽

Brown Adipose ◽

Whole Body Cooling ◽

Saline Vehicle

Neurons in the rostral raphe pallidus (RPa) play an essential role in the regulation of sympathetically mediated metabolism and thermogenesis in brown adipose tissue (BAT). The presence of serotonergic neurons in the RPa that are retrogradely labeled following pseudorabies virus injections into BAT suggests that these neurons play a role in the regulation of BAT. In urethane/chloralose-anesthetized rats, whole body cooling decreased skin (−5.7 ± 2.3°C) and core (−1.3 ± 0.2°C) temperatures and resulted in an increase in BAT sympathetic nerve activity (SNA; +1,026 ± 344% of baseline activity). Serial microinjections of the 5-hydroxytryptamine (5-HT) receptor antagonist, methysergide (1.2 nmol/site), but not saline vehicle, into the intermediolateral cell column (IML) in spinal segments T2–T5 markedly attenuated the cooling-evoked increase in BAT SNA (remaining area under the curve, AUC: 36 ± 9% of naive cooling response). Microinjections of the 5-HT1A receptor antagonist, WAY-100635 (1.2 nmol/site), or the 5-HT7 receptor antagonist, SB-269970 (1.2 nmol/site), into the T2–T5 IML also attenuated the cold-evoked increase in BAT SNA (remaining activity at peak inhibition: 47 ± 8% and 39 ± 12% of the initial cold-evoked response, respectively). The increases in BAT SNA evoked by microinjection of N-methyl-d-aspartate (NMDA) (12 pmol) or bicuculline (30 pmol) into the RPa were attenuated following microinjections of methysergide, but not saline vehicle, into the T2–T5 IML (NMDA remaining AUC, 64 ± 13% of naive response; bicuculline remaining AUC, 52 ± 5% of naive response). These results are consistent with our earlier demonstration of a potentiating effect of 5-HT within the IML on BAT SNA and indicate that activation of 5-HT1A and 5-HT7 receptors in the spinal cord contributes to increases in BAT SNA and thermogenesis.

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Absence of Intracellular Ion Channels TPC1 and TPC2 Leads to Mature-Onset Obesity in Male Mice, Due to Impaired Lipid Availability for Thermogenesis in Brown Adipose Tissue

Endocrinology ◽

10.1210/en.2014-1766 ◽

2015 ◽

Vol 156 (3) ◽

pp. 975-986 ◽

Cited By ~ 13

Author(s):

Pamela V. Lear ◽

David González-Touceda ◽

Begoña Porteiro Couto ◽

Patricia Viaño ◽

Vanessa Guymer ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Male Mice ◽

Wild Type ◽

Interscapular Brown Adipose Tissue ◽

Brown Adipose ◽

Beige Adipocytes ◽

Transient Receptor

Abstract Intracellular calcium-permeable channels have been implicated in thermogenic function of murine brown and brite/beige adipocytes, respectively transient receptor potential melastin-8 and transient receptor potential vanilloid-4. Because the endo-lysosomal two-pore channels (TPCs) have also been ascribed with metabolic functionality, we studied the effect of simultaneously knocking out TPC1 and TPC2 on body composition and energy balance in male mice fed a chow diet. Compared with wild-type mice, TPC1 and TPC2 double knockout (Tpcn1/2−/−) animals had a higher respiratory quotient and became obese between 6 and 9 months of age. Although food intake was unaltered, interscapular brown adipose tissue (BAT) maximal temperature and lean-mass adjusted oxygen consumption were lower in Tpcn1/2−/− than in wild type mice. Phosphorylated hormone-sensitive lipase expression, lipid density and expression of β-adrenergic receptors were also lower in Tpcn1/2−/− BAT, whereas mitochondrial respiratory chain function and uncoupling protein-1 expression remained intact. We conclude that Tpcn1/2−/− mice show mature-onset obesity due to reduced lipid availability and use, and a defect in β-adrenergic receptor signaling, leading to impaired thermogenic activity, in BAT.

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Caloric intake and Na+-K+-ATPase: differential regulation by alpha 1- and beta-noradrenergic receptors

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1984.247.3.r449 ◽

1984 ◽

Vol 247 (3) ◽

pp. R449-R455 ◽

Cited By ~ 1

Author(s):

A. C. Swann

Keyword(s):

Adipose Tissue ◽

Weight Gain ◽

Atpase Activity ◽

Brown Adipose Tissue ◽

Receptor Antagonist ◽

Caloric Intake ◽

Cafeteria Diet ◽

Metabolic Efficiency ◽

Brown Adipose ◽

Caloric Consumption

This study examined the effects of diet and treatment with noradrenergic receptor antagonists on weight gain and indices of Na+-K+-adenosine triphosphatase (ATPase) activity in the rat. When rats were fed a palatable cafeteria diet, their caloric consumption increased by about 80%, but they did not gain weight significantly. Ouabain binding and K+-p-nitrophenylphosphatase (NPPase) activity were increased in brown adipose tissue and soleus. These indices remained elevated after the rats were returned to a regular diet. When rats were fasted for 3 days, they lost weight, and the indices of Na+-K+-ATPase activity were markedly reduced in brown adipose tissue and soleus. After refeeding the fasted rats gained weight three times more rapidly than nonfasted rats with similar food intake. Indices of Na+-K+-ATPase activity remained as low as they had been when the rats were fasting. There was a consistent negative correlation between weight gain per calorie eaten and brown adipose tissue NPPase activity. Changes in Na+-K+-ATPase could therefore be involved in the effects of overfeeding and fasting on metabolic efficiency. Desmethylimipramine binding was increased by cafeteria diet and decreased by fasting, consistent with changes in sympathetic nervous system activity. Treatment with prazosin, an alpha 1-noradrenergic receptor antagonist, reduced Na+-K+-ATPase in either control or cafeteria diet-fed rats but did not alter the effect of cafeteria diet feeding. By contrast, treatment with propranolol, a beta-receptor antagonist, prevented the increase in Na+-K+-ATPase during cafeteria diet feeding.(ABSTRACT TRUNCATED AT 250 WORDS)

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The Endogenous Actions of Hypothalamic Peptides on Brown Adipose Tissue Thermogenesis in the Rat

Endocrinology ◽

10.1210/en.2009-1235 ◽

2010 ◽

Vol 151 (9) ◽

pp. 4236-4246 ◽

Cited By ~ 44

Author(s):

Aaron N. A. Verty ◽

Andrew M. Allen ◽

Brian J. Oldfield

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Food Intake ◽

Brown Adipose Tissue ◽

Receptor Antagonist ◽

Uncoupling Protein ◽

Bat Activity ◽

Brown Adipose ◽

Ucp1 Expression ◽

Fos Expression

Although the neuronal pathways within the hypothalamus critical in controlling feeding and energy expenditure and projecting to brown adipose tissue (BAT) have been identified and their peptidergic content characterized, endogenous action of such peptides in the control of BAT activity has not been elucidated. Here male Sprague Dawley rats received infusions of either melanin-concentrating hormone antagonist (SNAP-7941) (1 μg/μl · h), orexin A receptor antagonist (SB-334867-A; 1 μg/μl · h), combined SB-334867-A (1 μg/μl · h), and SNAP-7941 (1 μg/μl · h), or melanocortin-3/4 receptor antagonist (SHU9119) (1 μg/μl · h) via an indwelling cannula in the lateral ventricle attached to sc implanted osmotic minipump. BAT temperature, physical activity, body weight, food intake, and changes in uncoupling protein (UCP)-1 were measured. SB-334867-A and SNAP-7941 significantly increased BAT temperature and UCP1 expression and reduced food intake and body weight. Combined infusion of SB-334867-A and SNAP-7941 produced a pronounced response that was greater than the addition of the individual effects in all parameters measured. SHU9119 significantly decreased BAT temperature and UCP1 expression and increased feeding and body weight. In a second series of experiments, the effect of SB-334867-A and SNAP-7941 alone or combination on the expression of the Fos protein was determined. SB-334867-A and SNAP-7941 increased Fos expression in key hypothalamic and brainstem feeding-related regions. In combination, these antagonists produced a greater than additive elevation of Fos expression in most of the regions evaluated. These findings support a role for endogenous orexigenic and anorexigenic hypothalamic peptides acting in concert to create a thermogenic tone via BAT activity.

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Functional characterization of human brown adipose tissue metabolism

Biochemical Journal ◽

10.1042/bcj20190464 ◽

2020 ◽

Vol 477 (7) ◽

pp. 1261-1286 ◽

Cited By ~ 3

Author(s):

Marie Anne Richard ◽

Hannah Pallubinsky ◽

Denis P. Blondin

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Functional Characterization ◽

Human Infants ◽

Positron Emission ◽

Brown Adipose ◽

Treatment Of Obesity ◽

And Function

Brown adipose tissue (BAT) has long been described according to its histological features as a multilocular, lipid-containing tissue, light brown in color, that is also responsive to the cold and found especially in hibernating mammals and human infants. Its presence in both hibernators and human infants, combined with its function as a heat-generating organ, raised many questions about its role in humans. Early characterizations of the tissue in humans focused on its progressive atrophy with age and its apparent importance for cold-exposed workers. However, the use of positron emission tomography (PET) with the glucose tracer [18F]fluorodeoxyglucose ([18F]FDG) made it possible to begin characterizing the possible function of BAT in adult humans, and whether it could play a role in the prevention or treatment of obesity and type 2 diabetes (T2D). This review focuses on the in vivo functional characterization of human BAT, the methodological approaches applied to examine these features and addresses critical gaps that remain in moving the field forward. Specifically, we describe the anatomical and biomolecular features of human BAT, the modalities and applications of non-invasive tools such as PET and magnetic resonance imaging coupled with spectroscopy (MRI/MRS) to study BAT morphology and function in vivo, and finally describe the functional characteristics of human BAT that have only been possible through the development and application of such tools.

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