Disruption of Peripheral Leptin Signaling in Mice Results in Hyperleptinemia without Associated Metabolic Abnormalities

Although central leptin signaling appears to play a major role in the regulation of food intake and energy metabolism, the physiological role of peripheral leptin signaling and its relative contribution to whole-body energy metabolism remain unclear. To address this question, we created a mouse model (Cre-Tam mice) with an intact leptin receptor in the brain but a near-complete deletion of the signaling domain of leptin receptor in liver, adipose tissue, and small intestine using a tamoxifen (Tam)-inducible Cre-LoxP system. Cre-Tam mice developed marked hyperleptinemia (∼4-fold; P < 0.01) associated with 2.3-fold increase (P < 0.05) in posttranscriptional production of leptin. Whereas this is consistent with the disruption of a negative feedback regulation of leptin production in adipose tissue, there were no discernable changes in energy balance, thermoregulation, and insulin sensitivity. Hypothalamic levels of phosphorylated signal transducer and activator of transcription 3, neuropeptide expression, and food intake were not changed despite hyperleptinemia. The percentage of plasma-bound leptin was markedly increased (90.1–96 vs. 41.8–74.7%; P < 0.05), but plasma-free leptin concentrations remained unaltered in Cre-Tam mice. We conclude from these results that 1) the relative contribution to whole-body energy metabolism from peripheral leptin signaling is insignificant in vivo, 2) leptin signaling in adipocyte constitutes a distinct short-loop negative feedback regulation of leptin production that is independent of tissue metabolic status, and 3) perturbation of peripheral leptin signaling alone, although increasing leptin production, may not be sufficient to alter the effective plasma levels of leptin because of the counter-regulatory increase in the level of leptin binding protein(s).

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Adipose tissue NAD+ biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1909917116 ◽

2019 ◽

Vol 116 (47) ◽

pp. 23822-23828 ◽

Cited By ~ 8

Author(s):

Shintaro Yamaguchi ◽

Michael P. Franczyk ◽

Maria Chondronikola ◽

Nathan Qi ◽

Subhadra C. Gunawardana ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Metabolism ◽

Cold Exposure ◽

Energy Homeostasis ◽

Lipolytic Activity ◽

Whole Body ◽

Brown Adipocyte ◽

Nicotinamide Phosphoribosyltransferase ◽

Adaptive Thermogenesis ◽

Body Energy

Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD+ metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) and brown adipocyte-specific Nampt knockout (BANKO) mice because NAMPT is the rate-limiting NAD+ biosynthetic enzyme. We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of β-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely through inactivation of the NAD+–SIRT1–caveolin-1 axis, which limits an important fuel source fatty acid for BAT thermogenesis. These metabolic abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN), which bypasses the block in NAD+ synthesis induced by NAMPT deficiency. Although BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We also found NAMPT expression in supraclavicular adipose tissue (where human BAT is localized) obtained from human subjects increased during cold exposure, suggesting our finding in rodents could apply to people. These results demonstrate that adipose NAMPT-mediated NAD+ biosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism.

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Front cover: Cyanidin-3-glucoside increases whole body energy metabolism by upregulating brown adipose tissue mitochondrial function

Molecular Nutrition & Food Research ◽

10.1002/mnfr.201770111 ◽

2017 ◽

Vol 61 (11) ◽

pp. 1770111

Author(s):

Yilin You ◽

Xiaoxue Yuan ◽

Xiaomeng Liu ◽

Chen Liang ◽

Minghui Meng ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Metabolism ◽

Brown Adipose Tissue ◽

Mitochondrial Function ◽

Whole Body ◽

Front Cover ◽

Brown Adipose ◽

Body Energy

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Brown adipose tissue transplantation improves whole-body energy metabolism

Cell Research ◽

10.1038/cr.2013.64 ◽

2013 ◽

Vol 23 (6) ◽

pp. 851-854 ◽

Cited By ~ 116

Author(s):

Xiaomeng Liu ◽

Zongji Zheng ◽

Xiaoming Zhu ◽

Minghui Meng ◽

Lan Li ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Metabolism ◽

Brown Adipose Tissue ◽

Tissue Transplantation ◽

Whole Body ◽

Brown Adipose ◽

Body Energy

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Cyanidin-3-glucoside increases whole body energy metabolism by upregulating brown adipose tissue mitochondrial function

Molecular Nutrition & Food Research ◽

10.1002/mnfr.201700261 ◽

2017 ◽

Vol 61 (11) ◽

pp. 1700261 ◽

Cited By ~ 27

Author(s):

Yilin You ◽

Xiaoxue Yuan ◽

Xiaomeng Liu ◽

Chen Liang ◽

Minghui Meng ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Metabolism ◽

Brown Adipose Tissue ◽

Mitochondrial Function ◽

Whole Body ◽

Brown Adipose ◽

Body Energy

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Similar effects of NPY on energy metabolism and on plasma insulin in adrenalectomized ob/ob and lean mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.264.2.e226 ◽

1993 ◽

Vol 264 (2) ◽

pp. E226-E230 ◽

Cited By ~ 10

Author(s):

H. C. Walker ◽

D. R. Romsos

Keyword(s):

Adipose Tissue ◽

Oxygen Consumption ◽

Energy Metabolism ◽

Food Intake ◽

Plasma Insulin ◽

Whole Body ◽

Metabolic Responses ◽

Metabolic Rates ◽

Action Mechanisms ◽

Brown Adipose

A single intracerebroventricular (icv) injection of dexamethasone (250 ng) lowers brown adipose tissue (BAT) thermogenesis and whole body metabolic rates and raises plasma insulin concentrations within 30 min in adrenalectomized ob/ob mice with minimal effects in adrenalectomized lean mice. The present study was conducted to determine if intracerebroventricular neuropeptide Y (NPY), a neuropeptide regulated in part by glucocorticoids, would mimic effects of dexamethasone in these mice. NPY lowered BAT metabolism and whole body oxygen consumption and raised plasma insulin concentrations within 30 min in adrenalectomized ob/ob mice similarly to dexamethasone; but, unlike dexamethasone, NPY was as effective in modulating these metabolic responses in adrenalectomized lean mice as in ob/ob mice. Further, intracerebroventricular NPY increased food intake equally in both ob/ob and lean mice, whereas dexamethasone did not alter food intake during the 30 min postinjection period. These data are consistent with the hypothesis that NPY mediates some of the effects of intracerebroventricular dexamethasone action in ob/ob mice and that the divergence between ob/ob and lean mice lies in glucocorticoid control of NPY release/synthesis rather than in NPY action mechanisms.

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Angiopoietin-Like Growth Factor Involved in Leptin Signaling in the Hypothalamus

International Journal of Molecular Sciences ◽

10.3390/ijms22073443 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3443

Author(s):

Yunseon Jang ◽

Jun Young Heo ◽

Min Joung Lee ◽

Jiebo Zhu ◽

Changjun Seo ◽

...

Keyword(s):

Growth Factor ◽

Brain Regions ◽

Whole Body ◽

Signal Transducers ◽

Leptin Signaling ◽

Stat3 Phosphorylation ◽

Hypothalamic Regulation ◽

Induced Signal ◽

Body Energy ◽

Transcription 3

The hypothalamic regulation of appetite governs whole-body energy balance. Satiety is regulated by endocrine factors including leptin, and impaired leptin signaling is associated with obesity. Despite the anorectic effect of leptin through the regulation of the hypothalamic feeding circuit, a distinct downstream mediator of leptin signaling in neuron remains unclear. Angiopoietin-like growth factor (AGF) is a peripheral activator of energy expenditure and antagonizes obesity. However, the regulation of AGF expression in brain and localization to mediate anorectic signaling is unknown. Here, we demonstrated that AGF is expressed in proopiomelanocortin (POMC)-expressing neurons located in the arcuate nucleus (ARC) of the hypothalamus. Unlike other brain regions, hypothalamic AGF expression is stimulated by leptin-induced signal transducers and activators of transcription 3 (STAT3) phosphorylation. In addition, leptin treatment to hypothalamic N1 cells significantly enhanced the promoter activity of AGF. This induction was abolished by the pretreatment of ruxolitinib, a leptin signaling inhibitor. These results indicate that hypothalamic AGF expression is induced by leptin and colocalized to POMC neurons.

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The Role of AMPK Signaling in Brown Adipose Tissue Activation

Cells ◽

10.3390/cells10051122 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1122

Author(s):

Jamie I. van der van der Vaart ◽

Mariëtte R. Boon ◽

Riekelt H. Houtkooper

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Whole Body ◽

Ampk Signaling ◽

Mitochondrial Homeostasis ◽

Brown Adipose ◽

Metabolic Stresses ◽

Amp Activated Protein Kinase ◽

Body Energy

Obesity is becoming a pandemic, and its prevalence is still increasing. Considering that obesity increases the risk of developing cardiometabolic diseases, research efforts are focusing on new ways to combat obesity. Brown adipose tissue (BAT) has emerged as a possible target to achieve this for its functional role in energy expenditure by means of increasing thermogenesis. An important metabolic sensor and regulator of whole-body energy balance is AMP-activated protein kinase (AMPK), and its role in energy metabolism is evident. This review highlights the mechanisms of BAT activation and investigates how AMPK can be used as a target for BAT activation. We review compounds and other factors that are able to activate AMPK and further discuss the therapeutic use of AMPK in BAT activation. Extensive research shows that AMPK can be activated by a number of different kinases, such as LKB1, CaMKK, but also small molecules, hormones, and metabolic stresses. AMPK is able to activate BAT by inducing adipogenesis, maintaining mitochondrial homeostasis and inducing browning in white adipose tissue. We conclude that, despite encouraging results, many uncertainties should be clarified before AMPK can be posed as a target for anti-obesity treatment via BAT activation.

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Hepatic Crtc2 controls whole body energy metabolism via a miR-34a-Fgf21 axis

Nature Communications ◽

10.1038/s41467-017-01878-6 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 19

Author(s):

Hye-Sook Han ◽

Byeong Hun Choi ◽

Jun Seok Kim ◽

Geon Kang ◽

Seung-Hoi Koo

Keyword(s):

Energy Metabolism ◽

Whole Body ◽

Body Energy

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Adipose tissue in control of metabolism

Journal of Endocrinology ◽

10.1530/joe-16-0211 ◽

2016 ◽

Vol 231 (3) ◽

pp. R77-R99 ◽

Cited By ~ 188

Author(s):

Liping Luo ◽

Meilian Liu

Keyword(s):

Adipose Tissue ◽

Metabolic Pathways ◽

The Body ◽

The Other ◽

Whole Body ◽

Endocrine Organ ◽

Lipid Mobilization ◽

Adipose Tissue Dysfunction ◽

Body Energy ◽

Beige Adipose Tissue

Adipose tissue plays a central role in regulating whole-body energy and glucose homeostasis through its subtle functions at both organ and systemic levels. On one hand, adipose tissue stores energy in the form of lipid and controls the lipid mobilization and distribution in the body. On the other hand, adipose tissue acts as an endocrine organ and produces numerous bioactive factors such as adipokines that communicate with other organs and modulate a range of metabolic pathways. Moreover, brown and beige adipose tissue burn lipid by dissipating energy in the form of heat to maintain euthermia, and have been considered as a new way to counteract obesity. Therefore, adipose tissue dysfunction plays a prominent role in the development of obesity and its related disorders such as insulin resistance, cardiovascular disease, diabetes, depression and cancer. In this review, we will summarize the recent findings of adipose tissue in the control of metabolism, focusing on its endocrine and thermogenic function.

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