Lack of AR in LepRb Cells Disrupts Ambulatory Activity and Neuroendocrine Axes in a Sex-Specific Manner in Mice

Abstract Disorders of androgen imbalance, such as hyperandrogenism in females or hypoandrogenism in males, increase risk of visceral adiposity, type 2 diabetes, and infertility. Androgens act upon androgen receptors (AR) which are expressed in many tissues. In the brain, AR are abundant in hypothalamic nuclei involved in regulation of reproduction and energy homeostasis, yet the role of androgens acting via AR in specific neuronal populations has not been fully elucidated. Leptin receptor (LepRb)–expressing neurons coexpress AR predominantly in hypothalamic arcuate and ventral premammillary nuclei (ARH and PMv, respectively), with low colocalization in other LepRb neuronal populations, and very low colocalization in the pituitary gland and gonads. Deletion of AR from LepRb-expressing cells (LepRbΔAR) has no effect on body weight, energy expenditure, and glucose homeostasis in male and female mice. However, LepRbΔAR female mice show increased body length later in life, whereas male LepRbΔAR mice show an increase in spontaneous ambulatory activity. LepRbΔAR mice display typical pubertal timing, estrous cycles, and fertility, but increased testosterone levels in males. Removal of sex steroid negative feedback action induced an exaggerated rise in luteinizing hormone in LepRbΔAR males and follicle-stimulating hormone in LepRbΔAR females. Our findings show that AR can directly affect a subset of ARH and PMv neurons in a sex-specific manner and demonstrate specific androgenic actions in the neuroendocrine hypothalamus.

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Single-cell analysis reveals cellular heterogeneity and molecular determinants of hypothalamic leptin-receptor cells

10.1101/2020.07.23.217729 ◽

2020 ◽

Author(s):

N. Kakava-Georgiadou ◽

J.F. Severens ◽

A.M. Jørgensen ◽

K.M. Garner ◽

M.C.M Luijendijk ◽

...

Keyword(s):

Single Cell ◽

Leptin Receptor ◽

Single Cell Analysis ◽

Cell Types ◽

Cellular Heterogeneity ◽

Molecular Signature ◽

Neuronal Populations ◽

Hypothalamic Nuclei ◽

Satiety Hormone ◽

Multiple Cell

AbstractHypothalamic nuclei which regulate homeostatic functions express leptin receptor (LepR), the primary target of the satiety hormone leptin. Single-cell RNA sequencing (scRNA-seq) has facilitated the discovery of a variety of hypothalamic cell types. However, low abundance of LepR transcripts prevented further characterization of LepR cells. Therefore, we perform scRNA-seq on isolated LepR cells and identify eight neuronal clusters, including three uncharacterized Trh-expressing populations as well as 17 non-neuronal populations including tanycytes, oligodendrocytes and endothelial cells. Food restriction had a major impact on Agrp neurons and changed the expression of obesity-associated genes. Multiple cell clusters were enriched for GWAS signals of obesity. We further explored changes in the gene regulatory landscape of LepR cell types. We thus reveal the molecular signature of distinct populations with diverse neurochemical profiles, which will aid efforts to illuminate the multi-functional nature of leptin’s action in the hypothalamus.

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MAPK Erk5 in Leptin Receptor‒Expressing Neurons Controls Body Weight and Systemic Energy Homeostasis in Female Mice

Endocrinology ◽

10.1210/en.2019-00090 ◽

2019 ◽

Vol 160 (12) ◽

pp. 2837-2848 ◽

Cited By ~ 3

Author(s):

Tetsuhiro Horie ◽

Gyujin Park ◽

Yuka Inaba ◽

Emi Hashiuchi ◽

Takashi Iezaki ◽

...

Keyword(s):

Body Weight ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Metabolic Diseases ◽

Insulin Injection ◽

Long Term Memory ◽

Chow Diet ◽

Tissue Mass ◽

Female Mice ◽

Physiological Importance

Abstract Extracellular signal-regulated kinase 5 (Erk5), a member of the MAPK family, is specifically phosphorylated and activated by MAPK/Erk kinase-5. Although it has been implicated in odor discrimination and long-term memory via its expression in the central nervous system, little is known regarding the physiological importance of neuronal Erk5 in body weight and energy homeostasis. In the current study, systemic insulin injection significantly induced phosphorylation of Erk5 in the hypothalamus. Moreover, Erk5 deficiency in leptin receptor (LepR)‒expressing neurons led to an obesity phenotype, with increased white adipose tissue mass due to increased adipocyte size, only in female mice fed a normal chow diet. Furthermore, Erk5 deficiency in LepR-expressing neurons showed impaired glucose tolerance along with decreased physical activity, food intake, and energy expenditure. These results suggest that Erk5 controls body weight and systemic energy homeostasis probably via its expression in hypothalamic neurons in female mice, thereby providing a target for metabolic diseases such as obesity and type 2 diabetes mellitus.

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Central Regulation of Metabolism by Growth Hormone

Cells ◽

10.3390/cells10010129 ◽

2021 ◽

Vol 10 (1) ◽

pp. 129

Author(s):

Jose Donato ◽

Frederick Wasinski ◽

Isadora C. Furigo ◽

Martin Metzger ◽

Renata Frazão

Keyword(s):

Growth Hormone ◽

Energy Homeostasis ◽

Current Knowledge ◽

Metabolic Stress ◽

Wide Distribution ◽

Tissue Growth ◽

Neuronal Populations ◽

Hypothalamic Nuclei ◽

The Brain

Growth hormone (GH) is secreted by the pituitary gland, and in addition to its classical functions of regulating height, protein synthesis, tissue growth, and cell proliferation, GH exerts profound effects on metabolism. In this regard, GH stimulates lipolysis in white adipose tissue and antagonizes insulin’s effects on glycemic control. During the last decade, a wide distribution of GH-responsive neurons were identified in numerous brain areas, especially in hypothalamic nuclei, that control metabolism. The specific role of GH action in different neuronal populations is now starting to be uncovered, and so far, it indicates that the brain is an important target of GH for the regulation of food intake, energy expenditure, and glycemia and neuroendocrine changes, particularly in response to different forms of metabolic stress such as glucoprivation, food restriction, and physical exercise. The objective of the present review is to summarize the current knowledge about the potential role of GH action in the brain for the regulation of different metabolic aspects. The findings gathered here allow us to suggest that GH represents a hormonal factor that conveys homeostatic information to the brain to produce metabolic adjustments in order to promote energy homeostasis.

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Unsilencing of native LepRs in hypothalamic SF1 neurons does not rescue obese phenotype in LepR-deficient mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00111.2019 ◽

2019 ◽

Vol 317 (3) ◽

pp. R451-R460 ◽

Cited By ~ 4

Author(s):

Seraina S. Senn ◽

Christelle Le Foll ◽

Lynda Whiting ◽

Erika Tarasco ◽

Sonya Duffy ◽

...

Keyword(s):

Glucose Tolerance ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Metabolic Dysfunction ◽

Steroidogenic Factor 1 ◽

Enhanced Sensitivity ◽

Diet Induced Obesity ◽

Hypothalamic Nuclei ◽

Pancreatic Hormone ◽

Phosphorylated Stat3

Leptin receptor (LepR) signaling in neurons of the ventromedial nucleus of the hypothalamus (VMH), specifically those expressing steroidogenic factor-1 (SF1), have been proposed to play a key role in controlling energy balance. By crossing LepR-silenced (LepRloxTB) mice with those expressing SF1-Cre, we unsilenced native LepR specifically in the VMH and tested whether SF1 neurons in the VMH are critical mediators of leptin’s effect on energy homeostasis. LepRloxTB × SF1-Cre [knockout (KO)/Tg+] mice were metabolically phenotyped and compared with littermate controls that either expressed or were deficient in LepRs. Leptin-induced phosphorylated STAT3 was present in the VMH of KO/Tg+ mice and absent in other hypothalamic nuclei. VMH leptin signaling did not ameliorate obesity resulting from LepR deficiency in chow-fed mice. There was no change in food intake or energy expenditure when comparing complete LepR-null mice with KO/Tg+ mice, nor did KO/Tg+ mice show improved glucose tolerance. The presence of functional LepRs in the VMH mildly enhanced sensitivity to the pancreatic hormone amylin. When maintained on a high-fat diet (HFD), there was no reduction in diet-induced obesity in KO/Tg+ mice, but KO/Tg+ mice had improved glucose tolerance after 7 wk on an HFD compared with LepR-null mice. We conclude that LepR signaling in the VMH alone is not sufficient to correct metabolic dysfunction observed in LepR-null mice.

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The leptin-dependent and -independent melanocortin signaling system: regulation of feeding and energy expenditure

Journal of Endocrinology ◽

10.1677/joe-06-0144 ◽

2007 ◽

Vol 193 (1) ◽

pp. 1-9 ◽

Cited By ~ 47

Author(s):

Hiroyuki Shimizu ◽

Kinji Inoue ◽

Masatomo Mori

Keyword(s):

Energy Expenditure ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Signaling System ◽

Leptin Signaling ◽

Melanocyte Stimulating Hormone ◽

Hypothalamic Nuclei ◽

Hypothalamic Arcuate Nucleus ◽

Melanocortin Signaling ◽

The Brain

The brain hypothalamus coordinates extra-hypothalamic regions to maintain energy homeostasis through the regulation of food intake and energy expenditure. A number of anorexigenic and orexigenic molecules in the hypothalamic nuclei participate in the control of energy homeostasis. Leptin and pro-opiomelanocortin (POMC)-derived α-melanocyte-stimulating hormone are key anorectic molecules, and the leptin receptor and POMC gene are both expressed in the hypothalamic arcuate nucleus. Although it has been considered that melanocortin signaling is localized downstream to leptin signaling, data have accumulated to support the concept of a leptin-independent melanocortin signaling system. We focus on and review the melanocortin signaling system that functions dependently or independently of leptin signaling in the regulation of energy homeostasis.

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Liver-Specific Kisspeptin Deletion Impairs Energy Metabolism in Mice

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.900 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A440-A441

Author(s):

Bahaa Aloqaily ◽

Hyokjoon Kwon ◽

Sarmed Al-Samerria ◽

Ariel L Negron ◽

Fredric Edward Wondisford ◽

...

Keyword(s):

Insulin Secretion ◽

Glucose Homeostasis ◽

Energy Homeostasis ◽

Pubertal Development ◽

Glucose Production ◽

Ambulatory Activity ◽

Glucose Consumption Rate ◽

Male And Female ◽

Female Mice

Abstract Kisspeptin, a neuroendocrine protein critical for the control of pubertal development and fertility has been shown to be modulated by nutritional signals. While the secretion of kisspeptin from specific hypothalamic nuclei is well-known to regulate GnRH-mediated pubertal maturation and reproduction, it remains unclear what role peripheral kisspeptin, specifically of hepatic origin, plays in regulating metabolism and glucose homeostasis. To define the role of kisspeptin in the liver, we developed a novel Kiss1f/f mouse line and targeted liver-specific Kiss1 ablation by injecting a AAV8-TBG-iCre virus via the tail vein (LKiss1KO). Control mice included Kiss1f/f male and female mice injected with AAV-GFP (LKiss1WT). We previously showed that deletion of hepatic kisspeptin did not affect body weight, but resulted in decreased insulin secretion and glucose intolerance in both sexes. To clarify the effects of liver-specific Kiss1 knockout on insulin action and glucose homeostasis in vivo, we conducted hyperinsulinemic-euglycemic clamp studies three weeks after tail injections. We noted a sexual dimorphism in the glucose infusion rate (GIR), female mice have a higher GIR to maintain euglycemia associated with an elevated glucose consumption rate, suggesting that female mice are more insulin sensitive than male mice. However, the deletion of liver kisspeptin had no effect on the glucose production rate in either sex. Indirect calorimetry assessment was conducted 4 weeks post-injection. Both male and female LKiss1KO mice showed significantly higher oxygen consumption, carbon dioxide production, and increased energy expenditure as compared to the LKiss1WT groups. However, there were no differences in either the respiratory exchange ratio or total ambulatory activity among treatments. These findings clearly define a pivotal role for hepatic Kiss1 in the modulation of insulin secretion to maintain glucose homeostasis without modulating glucose production as well as in maintaining energy homeostasis in both male or female mice.

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Sex-specific regulation of weight and puberty by the Lin28/let-7 axis

Journal of Endocrinology ◽

10.1530/joe-15-0360 ◽

2015 ◽

Vol 228 (3) ◽

pp. 179-191 ◽

Cited By ~ 26

Author(s):

Christina Corre ◽

Gen Shinoda ◽

Hao Zhu ◽

Diana L Cousminer ◽

Christine Crossman ◽

...

Keyword(s):

Late Onset ◽

Pubertal Timing ◽

Association Studies ◽

Growth Patterns ◽

Age At Menarche ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Male And Female ◽

Female Mice ◽

Specific Manner

Growth and pubertal timing differ in boys and girls. Variants in/nearLIN28Bassociate with age at menarche (AAM) in genome-wide association studies and some AAM-related variants associate with growth in a sex-specific manner. Sex-specific growth patterns in response toLin28bperturbation have been detected in mice, and overexpression ofLin28ahas been shown to alter pubertal timing in female mice. To investigate further howLin28aandLin28baffect growth and puberty in both males and females, we evaluatedLin28bloss-of-function (LOF) mice andLin28again-of-function (GOF) mice. Because bothLin28aandLin28bcan act via the conserved microRNAlet-7, we also examinedlet-7GOF mice. As reported previously,Lin28bLOF led to lighter body weights only in male mice whileLin28aGOF yielded heavier mice of both sexes.Let-7GOF mice weighed less than controls, and males were more affected than females. Timing of puberty was assessed by vaginal opening (VO) and preputial separation (PS). MaleLin28bLOF and malelet-7GOF, but not female, mice displayed alteration of pubertal timing, with later PS than controls. In contrast, both male and femaleLin28aGOF mice displayed late onset of puberty. Together, these data point toward a complex system of regulation byLin28a,Lin28b, andlet-7, in whichLin28bandlet-7can impact both puberty and growth in a sex-specific manner, raising the possibility that this pathway may contribute to differential regulation of male and female growth and puberty in humans.

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The Neuronal Actions of Leptin and the Implications for Treating Alzheimer’s Disease

Pharmaceuticals ◽

10.3390/ph14010052 ◽

2021 ◽

Vol 14 (1) ◽

pp. 52

Author(s):

Kirsty Hamilton ◽

Jenni Harvey

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Hippocampal Formation ◽

Synaptic Function ◽

Receptor Expression ◽

Neuroprotective Actions ◽

Novel Target ◽

Leptin System

It is widely accepted that the endocrine hormone leptin controls food intake and energy homeostasis via activation of leptin receptors expressed on hypothalamic arcuate neurons. The hippocampal formation also displays raised levels of leptin receptor expression and accumulating evidence indicates that leptin has a significant impact on hippocampal synaptic function. Thus, cellular and behavioural studies support a cognitive enhancing role for leptin as excitatory synaptic transmission, synaptic plasticity and glutamate receptor trafficking at hippocampal Schaffer collateral (SC)-CA1 synapses are regulated by leptin, and treatment with leptin enhances performance in hippocampus-dependent memory tasks. Recent studies indicate that hippocampal temporoammonic (TA)-CA1 synapses are also a key target for leptin. The ability of leptin to regulate TA-CA1 synapses has important functional consequences as TA-CA1 synapses are implicated in spatial and episodic memory processes. Moreover, degeneration is initiated in the TA pathway at very early stages of Alzheimer’s disease, and recent clinical evidence has revealed links between plasma leptin levels and the incidence of Alzheimer’s disease (AD). Additionally, accumulating evidence indicates that leptin has neuroprotective actions in various AD models, whereas dysfunctions in the leptin system accelerate AD pathogenesis. Here, we review the data implicating the leptin system as a potential novel target for AD, and the evidence that boosting the hippocampal actions of leptin may be beneficial.

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Distinct Changes in Gut Microbiota Are Associated with Estradiol-Mediated Protection from Diet-Induced Obesity in Female Mice

Metabolites ◽

10.3390/metabo11080499 ◽

2021 ◽

Vol 11 (8) ◽

pp. 499

Author(s):

Kalpana D. Acharya ◽

Hye L. Noh ◽

Madeline E. Graham ◽

Sujin Suk ◽

Randall H. Friedline ◽

...

Keyword(s):

Gut Microbiota ◽

Energy Homeostasis ◽

Whole Body ◽

Glucose Turnover ◽

Female Mice ◽

Adult Mice ◽

Diet Induced Obesity ◽

Metabolic Dysregulation ◽

Regulation Of Metabolism ◽

Junction Protein

A decrease in ovarian estrogens in postmenopausal women increases the risk of weight gain, cardiovascular disease, type 2 diabetes, and chronic inflammation. While it is known that gut microbiota regulates energy homeostasis, it is unclear if gut microbiota is associated with estradiol regulation of metabolism. In this study, we tested if estradiol-mediated protection from high-fat diet (HFD)-induced obesity and metabolic changes are associated with longitudinal alterations in gut microbiota in female mice. Ovariectomized adult mice with vehicle or estradiol (E2) implants were fed chow for two weeks and HFD for four weeks. As reported previously, E2 increased energy expenditure, physical activity, insulin sensitivity, and whole-body glucose turnover. Interestingly, E2 decreased the tight junction protein occludin, suggesting E2 affects gut epithelial integrity. Moreover, E2 increased Akkermansia and decreased Erysipleotrichaceae and Streptococcaceae. Furthermore, Coprobacillus and Lactococcus were positively correlated, while Akkermansia was negatively correlated, with body weight and fat mass. These results suggest that changes in gut epithelial barrier and specific gut microbiota contribute to E2-mediated protection against diet-induced obesity and metabolic dysregulation. These findings provide support for the gut microbiota as a therapeutic target for treating estrogen-dependent metabolic disorders in women.

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Adiponectin receptors are expressed in hypothalamus and colocalized with proopiomelanocortin and neuropeptide Y in rodent arcuate neurons

Journal of Endocrinology ◽

10.1677/joe-08-0348 ◽

2008 ◽

Vol 200 (1) ◽

pp. 93-105 ◽

Cited By ~ 95

Author(s):

E Guillod-Maximin ◽

A F Roy ◽

C M Vacher ◽

A Aubourg ◽

V Bailleux ◽

...

Keyword(s):

Neuropeptide Y ◽

Energy Homeostasis ◽

Fluorescent Protein ◽

Peripheral Tissues ◽

Rat Hypothalamus ◽

Ampk Phosphorylation ◽

Hypothalamic Nuclei ◽

Green Fluorescent ◽

Amp Activated Protein Kinase

Adiponectin is involved in the control of energy homeostasis in peripheral tissues through Adipor1 and Adipor2 receptors. An increasing amount of evidence suggests that this adipocyte-secreted hormone may also act at the hypothalamic level to control energy homeostasis. In the present study, we observed the gene and protein expressions of Adipor1 and Adipor2 in rat hypothalamus using different approaches. By immunohistochemistry, Adipor1 expression was ubiquitous in the rat brain. By contrast, Adipor2 expression was more limited to specific brain areas such as hypothalamus, cortex, and hippocampus. In arcuate and paraventricular hypothalamic nuclei, Adipor1, and Adipor2 were expressed by neurons and astrocytes. Furthermore, using transgenic green fluorescent protein mice, we showed that Adipor1 and Adipor2 were present in pro–opiomelanocortin (POMC) and neuropeptide Y (NPY) neurons in the arcuate nucleus. Finally, adiponectin treatment by intracerebroventricular injection induced AMP-activated protein kinase (AMPK) phosphorylation in the rat hypothalamus. This was confirmed byin vitrostudies using hypothalamic membrane fractions. In conclusion, Adipor1 and Adipor2 are both expressed by neurons (including POMC and NPY neurons) and astrocytes in the rat hypothalamic nuclei. Adiponectin is able to increase AMPK phosphorylation in the rat hypothalamus. These data reinforced a potential role of adiponectin and its hypothalamic receptors in the control of energy homeostasis.

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