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. 2026 Jan 5;75(3):441–453. doi: 10.2337/db25-0388

Adipocyte Leptin Signaling Regulates Glycemia and Cardiovascular Function by Enhancing Brown Adipose Tissue Thermogenesis in Obese Male Mice

Yoichi Ono 1, Simone Kennard 1, Benjamin T Wall 1, Jing Ma 1, Eric J Belin de Chantemèle 1,2,✉
PMCID: PMC12928713  PMID: 41490102

Abstract

Although control of metabolism by leptin is primarily viewed as centrally mediated, leptin has also been shown to directly regulate adipocyte function. However, the impact of the peripheral effects of leptin on systemic metabolism, especially in the context of obesity, remains unclear. To address this question, we selectively restored adipocyte leptin receptor (LEPR) expression in obese male and female LEPR–conditional knockout mice. Adipocyte LEPR restoration did not affect body weight but selectively increased brown adipose tissue (BAT) mass in male mice. This was associated with increased energy expenditure, smaller BAT adipocytes, lower triglycerides content, and increased markers of browning and lipolysis exclusively in males. Additionally, adipocyte LEPR restoration enhanced the expression of markers of endothelial cells and angiogenesis in male mouse BAT, supporting increased local vascularization. Improved BAT function in males was also associated with lower HbA1c, better insulin sensitivity, reduced systolic blood pressure, decreased arterial stiffness, and improved endothelial function. Lastly, adipocyte LEPR restoration lowered circulating proinflammatory cytokines and reduced tissue inflammation in the aorta and heart, again in males only. These findings reveal a critical role for adipocyte leptin signaling in regulating BAT function and emphasize its importance in maintaining glycemic and cardiovascular health in males with obesity.

Article Highlights

  • Leptin is known to enhance brown adipose tissue (BAT) activity through sympathetic stimulation. However, in vitro studies suggest leptin could also act directly on adipocytes to promote lipolysis. Whether these peripheral effects of leptin are relevant to systemic metabolic control in obesity remains unclear.

  • We addressed this question by selectively restoring leptin receptor (LEPR) expression in adipocytes of obese LEPR–conditional knockout mice. LEPR restoration selectively enhanced BAT activity in male mice, which led to improved glycemic control and cardiovascular function.

  • These findings reveal a crucial role for BAT leptin signaling in regulating energy expenditure and glycemic and cardiovascular health, primarily in males.

Graphical Abstract

A schematic illustrates leptin action in brown adipose tissue in a male obese mouse expressing the leptin receptor in adipocytes only. Leptin signalling increases vascular endothelial growth factor A, angiopoietin, and transforming growth factor beta, raising vascular density. It also increases P R domain containing 16 and nuclear factor I A, leading to uncoupling protein 1 driven thermogenesis. The combined effects associate with decreased haemoglobin A 1 c, reduced blood pressure and arterial stiffness, and increased insulin sensitivity and endothelial dependent relaxation.

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Introduction

Initially viewed as a satiety hormone (1), the adipokine leptin has rapidly come to be recognized as a prime regulator of energy expenditure and metabolism (2). Interestingly, although the leptin receptor (LEPR) is expressed in all metabolic organs, including adipose tissue (3), leptin control of energy expenditure and metabolic function has primarily been reported to be centrally mediated. Notably, leptin-mediated increases in energy expenditure and lipolysis have been shown to involve central activation of the sympathetic nervous system, which stimulates β-adrenergic receptors on brown (BAT) and white adipose tissue (WAT) to promote the phosphorylation of hormone-sensitive lipase (HSL), formation of free fatty acids (FFAs), and activation of uncoupling protein 1 (UCP1) for heat production (4,5). Although this mechanism has been reported to be crucial for leptin-mediated increases in energy expenditure and lipolysis, recent in vitro evidence, gathered primarily in adipocytes in culture, suggests that leptin could also act directly on adipocytes to stimulate lipolysis (6). Indeed, previous experiments in rat white adipocytes have shown that leptin exposure enhances intracellular triglyceride (TG) hydrolysis and FFA incorporation into TGs, ultimately leading to increased net fatty acid efflux (6–9). However, the extent to which the direct effects of leptin on adipocyte metabolism contribute to systemic metabolic regulation and are conserved across all adipose depots, including BAT, in the context of obesity remains poorly defined. Moreover, it is unclear whether these mechanisms are equally operative in both sexes and whether leptin-induced improvements in adipocyte function confer cardiovascular benefits. To address these questions, we generated and characterized a novel obese mouse model with adipocyte-specific expression of LEPR, enabling targeted assessment of metabolic and cardiovascular consequences of adipocyte-restricted leptin signaling in the context of obesity.

Research Design and Methods

Models and Animals

Male and female obese mice with selective expression of LEPR in adipocytes were generated by crossing LEPRloxTB mice (provided by Dr. Joel Elmquist, University of Texas Southwestern Medical Center) with mice expressing Cre recombinase under the control of the adiponectin promoter (APN-Cre mice; strain no. 028020; The Jackson Laboratory). The LEPRloxTB model includes a transcriptional blockade cassette inserted after exon 16, disrupting the expression of both the short form (LEPRa), which has limited signaling capacity, and the long signaling-competent form (LEPRb), while leaving the soluble form (LEPRe) intact, because all these isoforms share the same promoter and upstream exons (10). The targeted genetic construct was confirmed by genotyping. Experiments were conducted in 14–17-week-old littermates fed a standard mouse chow (Teklad Global 18% Protein Rodent Diet) and provided water ad libitum. LEPRloxTB × APN-Cre mice were compared with sex- and age-matched LEPRloxTB mice. In addition, wild-type C57BL/6J mice (3–4 months old; both sexes), maintained in our in-house colony, were used for comparison of physiological LEPR expression levels in adipose tissues. All animal investigations were conducted in an American Association for the Accreditation of Laboratory Animal Care–accredited facility, with experiments approved by the Institutional Animal Care and Use Committee (protocol 2011-0108). For euthanasia procedures, mice were first anesthetized in a closed chamber using 5% isoflurane (1 L/min O2) before decapitation. Isolated tissues were snap frozen in liquid nitrogen before storage at −80°C.

Indirect Calorimetry and Body Composition

Body composition was determined in a subset of mice using the Bruker Minispec LF90 time domain–nuclear magnetic resonance analyzer. Indirect calorimetric measurements, including oxygen consumption, carbon dioxide respiration, respiratory exchange ratio, heat production, and food and water intake, were measured in plexiglass respiratory chambers using open-circuit Oxymax Comprehensive Lab Animal Monitoring Systems (Columbus Instruments). Noninvasive measurements of the metabolic parameters described earlier were monitored every 5–10 min for 3 days after a 24-h acclimation period as previously described (11).

Infrared Thermography for BAT Activity

Fur over the interscapular region was carefully shaved. Each mouse was then placed in a small cage and allowed to acclimate for 20 min. Thermal images were acquired using the FLIR T540 camera, and the interscapular region of interest was analyzed using FLIR Tools software (version 6.4) to quantify BAT temperature.

HbA1c and Glucose and Insulin Tolerance Tests

HbA1c was measured at the time of sacrifice using the A1CNow Self Check system (PTS Diagnostics, Whitestown, IN). Values below the measurable range, shown as <4.0% on the device, were recorded as 3.9%. Intraperitoneal glucose (IPGTTs) and insulin tolerance tests (ITTs) were conducted in conscious fasted mice (16-h fasting for IPGTTs; 6-h fasting for ITTs). Blood glucose levels were measured at baseline and 15, 30, 60, 90, and 120 min after an intraperitoneal bolus injection of glucose (1 g/kg body weight) for IPGTTs and at the same time points plus an additional measurement 45 min after insulin injection (4 units/kg body weight; 100 units/mL Humulin R insulin; Eli Lilly, Indianapolis, IN) for ITTs.

Measurements of Plasma Insulin, Leptin, TG, and Cytokine Levels

Plasma leptin (EZML-82K kit; Millipore Sigma), insulin (EMINS kit; Thermo Fisher Scientific), and TGs (L-Type Triglyceride M Enzyme Color A and B and Multi-Calibrator Lipid; Fujifilm) were measured by ELISA following the manufacturers’ instructions. TGs were also measured in BAT homogenates. Plasma cytokines, including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1α (IL-1α), IL-1β, IL-6, IL-10, IL-17A, IL-12p70, granulocyte-macrophage colony-stimulating factor, IL-23, IFN-β, MCP-1, and IL-27, were measured using the Mouse Inflammation 13-Plex Panel (cat. no. FbBA243) as previously described (12).

Additional commonly used experimental procedures, including measurement of blood pressure pulse wave velocity (PWV), morphological characterization of the BAT, vascular reactivity studies, quantitative RT-PCR (qRT-PCR) analysis, and Western blotting, are described in the Supplementary Material.

Statistical Analysis

All data are presented as mean ± SEM. Whenever applicable, an unpaired two-sample t test, one-way ANOVA followed by Dunnett post hoc test, or two-way ANOVA followed by Sidak post hoc test was used to analyze data (GraphPad Prism 10; GraphPad Software, Inc., La Jolla, CA). P values or multiple-comparison adjusted P values < 0.05 were considered significant.

Data and Resource Availability

Supporting data are available from the corresponding author on reasonable request.

Results

Selective Restoration of Adipocyte LEPR Improves BAT Structure and Function in Male Mice Only

To confirm selective adipocyte LEPR restoration in LEPRloxTB × APN-Cre mice, LEPR transcript levels were quantified by qRT-PCR in the heart, liver, muscle, hypothalamus, brain without hypothalamus, BAT, subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and perivascular adipose tissue (PVAT). As shown in Supplementary Figs. 1A and 2A, male and female LEPRloxTB × APN-Cre mice expressed the long (LEPRb) and short (LEPRa) forms of LEPR in all fat depots but not in other organs, confirming the selectivity of our mouse model. Reexpression of LEPR in LEPRloxTB × APN-Cre mice had only minor effects on the circulating form (LEPRe) (Supplementary Figs. 1C and 2C), the expression of which was mostly unaffected, with the exception of male SAT, which exhibited a significant increase, and female liver, muscle, and BAT, which showed significant reductions. Consistent with the transcript data, BAT LEPRb protein expression was significantly increased in both sexes (Supplementary Fig. 3A). Interestingly, male LEPRloxTB × APN-Cre mice exhibited fourfold and 62-fold increases in BAT Leprb and Lepra expression, respectively, compared with female counterparts. Other adipose tissue did not exhibit sex differences in either Leprb or Lepra expression (Supplementary Fig. 3B). Analysis of interadipose tissue differences in both males and females revealed that although Leprb expression was restored to a similar extent in BAT, VAT, and PVAT, only SAT exhibited greater restoration in expression compared with BAT in both sexes. However, Lepra expression did not differ between adipose depots in either males or females (Supplementary Fig. 3C). To assess the level of Lepr reexpression, obese LEPRloxTB × APN-Cre mice were compared with lean wild-type mice. Male and female LEPRloxTB × APN-Cre mice exhibited ∼14-fold and sixfold greater BAT Leprb levels, respectively, but similar BAT Lepra levels compared with lean wild-type C57BL/6 mice (Supplementary Fig. 3D). Lastly, lean male and female wild-type C57BL/6 mice presented with no differences in BAT Leprb or Lepra levels (Supplementary Fig. 3D).

In male mice, selective restoration of adipocyte LEPR led to a significant increase in BAT weight, with no alteration in other fat pad weights, total body weight, or total fat volume (Fig. 1A and B). In females, restoration of adipose tissue LEPR selectively reduced SAT and increased the percentage of fluid volume (Fig. 1A and B). These minor changes in body composition were observed without changes in circulating leptin levels (Fig. 1C), food intake, fluid consumption, or activity, in either male or female mice (Supplementary Fig. 4A and B). BAT is a central regulator of energy expenditure, the weight of which correlates positively with activity (13). Therefore, we used indirect calorimetry to assess the effects of adipocyte LEPR reexpression on energy expenditure. Selective expression of LEPR in adipose tissue increased oxygen consumption, carbon dioxide production, and heat production in male mice only, reflecting an increase in energy expenditure (Fig. 1D). This increase in heat production was mainly localized in BAT, as demonstrated by infrared thermography (Fig. 1E). However, LEPR reexpression did not alter the respiratory exchange ratio.

Figure 1.

A multi-panel figure presents quantitative results labelled A to E comparing male and female groups across multiple measurements. Bar charts show total weight in grams, brown adipose tissue percentage, visceral adipose tissue percentage, subcutaneous adipose tissue percentage, fat percentage, lean percentage, fluid percentage, and plasma leptin in nanograms per millilitre. Line plots display oxygen consumption, carbon dioxide production, respiratory exchange ratio, and heat in kilocalories per kilogram per hour across days. Thermal images and a bar chart show surface temperature in degrees Celsius for two experimental groups.

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Restoration of adipocyte LEPR enhanced BAT weight and thermogenic activity in male mice only. A and B: Body and tissue weight, expressed as percentage of total body weight, measured by nuclear magnetic resonance at sacrifice. C: Plasma leptin levels. D: Measurements of oxygen consumption (VO2), carbon dioxide production (VCO2), and heat production in LEPRloxTB and LEPRloxTB × APN-Cre male and female mice, conducted via indirect calorimetry. E: Temperature of the interscapular BAT region measured by infrared thermography in male LEPRloxTB and LEPRloxTB × APN-Cre mice. Blue, green, red, and purple bars or lines represent male LEPRloxTB, male LEPRloxTB × APN-Cre, female LEPRloxTB, and female LEPRloxTB × APN-Cre mice, respectively. Data are presented as mean ± SEM (n = 3–16). *P < 0.05, **P < 0.01.

Based on the selective effects of LEPR restoration on BAT size and function, we investigated BAT morphology. Adipose tissue LEPR restoration decreased BAT adipocyte size and increased adipocyte density in males (Fig. 2A) but not in females (Supplementary Fig. 5A). We also used qRT-PCR to quantify genes related to browning, including Ucp1, Prdm16, and Nfia (14). Adipocyte LEPR restoration increased Ucp1, Prdm16, Nfia, and Ppargc1a expression in male (Fig. 2B) but not in female mice (Supplementary Fig. 5B), supporting an increase in browning in males only. Dio2 and Adrb3 expression remained unchanged, indicating that sympathetic activation or Dio2-mediated mechanisms were unlikely to account for the increase in Ucp1 (Fig. 2B). Consistent with the transcript data, UCP1 expression was also elevated at the protein level in male LEPRloxTB × APN-Cre mice (Fig. 2C). TOM20, a protein marker of mitochondrial mass, was significantly increased in LEPR-reexpressing male mouse BAT. However, mtDNA/nuclear DNA was not significantly altered (Supplementary Fig. 6A), suggesting an increase in mitochondrial function rather than an increase in mitochondrial number in male LEPRloxTB × APN-Cre mice. Consistent with these observations, phosphorylated STAT3 activation was significantly enhanced in male mouse BAT by the restoration of adipocyte LEPR but remained unchanged in female mouse BAT (Fig. 2D and Supplementary Fig. 6B). LEPR restoration led to no increase in browning markers in SAT, VAT, or PVAT (Supplementary Fig. 6C), suggesting primarily BAT-specific effects. However, adipocyte LEPR restoration induced a marked decrease in browning markers (Ucp1 and Nfia) in female mouse PVAT. Because lipolysis increases UCP1 activity and browning (15), we measured circulating and BAT TG levels. We also assessed the degree of activation of adipose TG lipase and HSL activity by evaluating their levels of phosphorylation. As reported in Fig. 2E and Supplementary Fig. 6D, reexpression of adipocyte LEPR reduced BAT TG levels without altering plasma TGs in male mice only. Furthermore, reexpression of adipocyte LEPR significantly increased HSL activity in males (Fig. 2F), which supports an increase in lipolysis in male mouse BAT.

Figure 2.

A multi-panel figure compares brown adipose tissue features between male L E P R l o x T B and male L E P R l o x T B x A P N C r e groups. Microscopy views show differences in adipocyte size and density, with charts quantifying mean adipocyte area in square micrometres, adipocyte number per one thousand square millimetres, relative frequency by cell size, gene fold change, protein expression levels, and triglyceride measurements.

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Restoration of adipocyte LEPR induced browning in male mouse BAT. A: Representative section of BAT from male LEPRloxTB and LEPRloxTB × APN-Cre mice stained with hematoxylin-eosin staining from which adipocyte size, density, and frequency of distribution were measured. Scale bars indicate 50 μm. B: qPCR quantification of browning markers UCP1, PRDM16, and NFIA in male mouse BAT. C: Representative Western blots and quantification of UCP1 in male mouse BAT. D: Representative Western blots and quantification of total and phosphorylated STAT3 (pSTAT3). E: Plasma and BAT TG levels in males. F: Representative Western blots and quantification of total and phosphorylated HSL (pHSL) and adipose TG lipase (pATGL). Blue and green bars represent male LEPRloxTB and male LEPRloxTB × APN-Cre mice, respectively. Data are presented as mean ± SEM (n = 4–9). *P < 0.05, **P < 0.01.

Selective Restoration of Adipocyte LEPR Increases BAT Vascularization

Evidence indicates that BAT perfusion and vascular density contribute to the regulation of its activity (16). Therefore, we measured indices of vascular density in LEPRloxTB × APN-Cre mice. We quantified markers of endothelial cell numbers, including isolectin B4, CD31, and Cdh5, and markers of angiogenesis: vascular endothelial growth factor A (Vegfa), hypoxia-inducible factor-1 (Hif-1), Hif-2, angiopoietin-1 (Angpt1), Angpt2, and transforming growth factor-β (Tgf-β). All these markers were increased in male LEPRloxTB × APN-Cre mice compared with LEPRloxTB mice, supporting greater vascular density and increased angiogenesis in the BAT of male mice (Fig. 3A–C). LEPR reexpression did not lead to an increase in markers of angiogenesis in female LEPRloxTB × APN-Cre mice (Supplementary Fig. 7).

Figure 3.

A multi-panel figure compares brown adipose tissue vascular features between male L E P R l o x T B and male L E P R l o x T B x A P N C r e groups. Microscopy panels show nuclear staining and isolectin B 4 positive structures, with a bar chart quantifying isolectin positive area as a percentage of total area. Immunoblot panels show C D 31 protein normalised to beta actin. Bar charts display fold change of vascular and hypoxia related genes in brown adipose tissue.

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Restoration of adipocyte LEPR enhanced angiogenesis and vascular stabilization. A: Representative sections of BAT from LEPRloxTB and LEPRloxTB × APN-Cre mice stained for isolectin B4 and quantified. Data are presented as the ratio of isolectin B4 to the total area. Scale bars indicate 60 μm. B: Representative Western blots and quantification of BAT CD31 protein levels. C: qPCR quantification of endothelial and angiogenesis markers. Blue and green bars represent male LEPRloxTB and male LEPRloxTB × APN-Cre mice, respectively. Data are presented as mean ± SEM (n = 3–9). *P < 0.05, **P < 0.01, ***P < 0.001.

LEPR Restoration in Adipocytes Improves Glycemic Control

BAT plays a key role in systemic glycemic control. Therefore, we assessed glucose and insulin sensitivity in LEPRloxTB and LEPRloxTB × APN-Cre mice. Restoration of adipocyte LEPR significantly lowered HbA1c and plasma insulin levels in male (Fig. 4A and B) but not in female mice (Supplementary Fig. 8A and B). Glucose clearance during IPGTTs was not markedly improved in either sex (Fig. 4C and Supplementary Fig. 8C). However, a significantly improved insulin response was observed in male LEPRloxTB × APN-Cre mice only (Fig. 4D and Supplementary Fig. 8D). Enhanced glycemic control in male LEPR-restored mice could be supported by increased phosphorylated AKT (pAKT)/AKT in BAT. In contrast, no changes were observed in muscle pAKT/AKT or in Glut4 expression in adipose tissue or muscle (Fig. 4E and F).

Figure 4.

Immunoblots and accompanying bar charts show phosphorylated AKT normalized to total AKT and total AKT normalized to the loading control vinculin in muscle and brown adipose tissue. Additional bar graphs show glucose transporter 4 (GLUT4) fold change among subcutaneous, brown, and visceral adipose depots as well as muscle.

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Restoration of adipocyte LEPR improved insulin sensitivity and glucose metabolism in male mice. A and B: HbA1c (A) and plasma insulin (B) levels. C: Blood glucose response to IPGTT and area under the curve (AUC) quantification. D: Blood glucose response to ITT and AUC quantification. E: Representative Western blots and quantification of total and pAKT. F: qPCR quantification of GLUT4 in insulin-sensitive tissues such as muscle, BAT, SAT, and VAT. Blue and green bars represent male LEPRloxTB and male LEPRloxTB × APN-Cre mice, respectively. Data are presented as mean ± SEM (n = 5–14). *P < 0.05.

LEPR Restoration in Adipocytes Improves Cardiovascular Function

Consistent with the improved glycemic control, systolic blood pressure (BP) and arterial stiffness (PWV) were significantly reduced in LEPRloxTB × APN-Cre male mice (Fig. 5A and B). Furthermore, restoration of adipocyte LEPR significantly improved endothelium-dependent relaxation, assessed by acetylcholine-mediated dilatation, without altering endothelium-independent relaxation measured in response to sodium nitroprusside in male mice (Fig. 5C and D). However, in female mice, adipocyte LEPR reexpression did not improve systolic BP, PWV, or endothelial function (Supplementary Fig. 9A–D). Vascular contractility to depolarization (KCl) and a1-adrenergic receptor activation (phenylephrine) remained intact in both male and female LEPRloxTB × APN-Cre mice (Fig. 5E and F and Supplementary Fig. 9E and F).

Figure 5.

A multi-panel figure compares vascular measurements between male L E P R l o x T B and male L E P R l o x T B x A P N C r e groups. Bar charts show systolic blood pressure in millimetres of mercury and pulse wave velocity in metres per second. Line plots show relaxation responses to acetylcholine and sodium nitroprusside across log molar concentrations. Additional panels show potassium chloride induced contraction in grams and phenylephrine induced contraction percentage across log molar concentrations.

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Restoration of adipocyte LEPR improved cardiovascular function, including BP, arterial stiffness, and endothelial function, in male mice. A: Systolic BP measured by tail-cuff method. B: PWV. C–F: Wire myograph analysis of aorta: endothelium-dependent (C) and -independent relaxation (D) and contraction induced by potassium chloride (KCl; 80 mmol/L) (E) and phenylephrine (Phe) (F). Blue and green bars represent male LEPRloxTB and male LEPRloxTB × APN-Cre mice, respectively. Data are presented as mean ± SEM (n = 5–11). *P < 0.05. ACh, acetylcholine; SNP, sodium nitroprusside.

LEPR Restoration in Adipocytes Suppresses Cardiovascular Inflammation

To assess the extent of the beneficial effects of the improved metabolic function in LEPRloxTB × APN-Cre mice, we quantified circulating and tissue markers of inflammation. Restoration of adipocyte LEPR significantly reduced plasma TNF-α, IL-1β, and IFN-γ and led to a trend toward reduction in IL-17A in male mice (Fig. 6A). This reduction in circulating proinflammatory cytokines in male LEPRloxTB × APN-Cre mice was associated with a decrease in vascular (aorta) and cardiac markers of oxidative stress and inflammation (Nox2, Nox4, and Tnf-α), immune cell adhesion (Vcam1 and Icam1), macrophage infiltration (F4/80), and markers of M1 macrophage activation (inos/Cd206) (Fig. 6B and C). Restoration of adipocyte LEPR in female mice did not improve plasma or tissue markers of inflammation (Supplementary Fig. 10A–C). The ameliorated systemic and local inflammation observed exclusively in male LEPRloxTB × APN-Cre mice was associated with increases in the expression of BAT-derived cardioprotective batokines (17,18), including fibroblast growth factor 21 (FGF21) and neuregulin 4 (NRG4) (Fig. 6D). No alterations in BAT Fgf21 or Nrg4 were reported in female LEPRloxTB × APN-Cre mice (Supplementary Fig. 10D). Although VAT and SAT showed no significant changes, BAT exhibited increased expression of inflammatory markers, such as Tnf-α and F4/80 (Supplementary Fig. 11).

Figure 6.

A multi-panel figure presents inflammatory and metabolic markers comparing male L E P R l o x T B and male L E P R l o x T B x A P N C r e groups. Bar charts show plasma cytokine concentrations in picograms per millilitre, including tumour necrosis factor alpha, interleukins, interferons, and colony stimulating factors. Additional bar charts show fold change of oxidative stress, inflammatory, and adhesion markers in aorta and heart tissue. A final panel shows brown adipose tissue fold change of fibroblast growth factor 21 and neuregulin 4.

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Restoration of adipocyte LEPR reduced systemic and tissue inflammation in male mice. A–C: Plasma cytokine (A), aorta (B), and heart (C) quantification of local inflammation via qPCR analysis. D: qPCR quantification of Fgf21 and Nrg4 in BAT. Blue and green bars represent male LEPRloxTB and male LEPRloxTB × APN-Cre mice, respectively. Data are presented as mean ± SEM (n = 4–12). *P < 0.05, **P < 0.01, ***P < 0.001.

Discussion

To test the potential direct role of adipose leptin signaling in controlling energy expenditure and metabolism, we generated obese mice with selective expression of LEPR in adipocytes. While characterizing the phenotype of these animals, we observed no significant alterations in body composition but a significant increase in male BAT mass accompanied by an increase in energy expenditure, reduction in BAT adipocyte size, greater BAT adipocyte density, enhanced lipolysis, and elevated BAT vascular density in male mice only. Remarkably, the male-specific improved BAT structure and function were associated with ameliorated insulin sensitivity and HbA1c, which likely contributed to ameliorated cardiovascular function, reflected by decreased BP, reduced arterial stiffness, and enhanced endothelium-dependent relaxation in males. Relevant to these findings are the mouse model of selective adipose leptin signaling, the selective effects of leptin on BAT, the sex specificity of the mechanism, and the cardiovascular benefits of restoring adipose leptin signaling.

To evaluate the specific effect of adipocyte leptin signaling on metabolism, we took advantage of the conditional LEPR-knockout mice in which LEPR could be restored in tissues of interest. Using this model and an adipocyte Cre line, we restored LEPRb and LEPRa expression exclusively in adipose depots of both male and female mice. Adipose Lepra levels were restored to levels matching those of lean sex-matched wild-type control mice, whereas the only known functional and signaling receptor, Leprb, was reexpressed to levels six- and 14-fold higher, respectively, in female and male mice than in the BAT of lean wild-type animals. These levels may appear supraphysiological. However, because the effects of obesity on BAT LEPRb levels are unknown, a comparison with an alternative model of obesity would provide a clearer assessment of their pathophysiological relevance. Nevertheless, this potential limitation does not diminish the significance of the model, because LEPRloxTB × APN-Cre mice offer a unique opportunity to delineate the specific contribution of adipocyte leptin signaling in the setting of severe obesity and diabetes and, importantly, in the absence of central leptin action. Given the limited knowledge of the function of LEPRa, which lacks intracellular signaling (10), all the effects reported in the current study have been attributed to LEPRb.

Remarkably, although LEPRloxTB × APN-Cre mice exhibited a restoration of LEPR in all adipose depots, enhanced thermogenic activity was reported exclusively in BAT and, more specifically, in male BAT. These findings are consistent with the observations of Pereira et al. (19), showing in the exact same mouse model that adipocyte LEPR restoration did not alter WAT function, but in contradiction with their findings, we observed an increase in male BAT UCP1 levels. The older age of their mice and the relatively superficial analysis of BAT function could potentially be the cause of the discrepancy between the two studies. Nevertheless, these two studies reporting no effects of LEPR restoration on WAT beiging or lipolysis tend to support a limited physiological role for the leptin-mediated lipolysis reported in rodent visceral and subcutaneous adipocytes in culture (6–9). In vitro experiments in children and adult human adipocytes in culture further minimize the role of leptin in WAT lipolysis (20). Consistent with the increase in BAT thermogenic activity, we also report that restoration of adipocyte LEPR expression in male mice reduced lipid droplet size and increased the ratio of phosphorylated HSL to HSL. Along with the reduction in BAT TG levels, these findings support that increasing BAT leptin signaling increases lipolysis. However, in the absence of a functional assay, these findings can only suggest, rather than conclusively demonstrate, that leptin signaling contributes to lipid mobilization in brown adipocytes.

Intriguingly, our findings raise the question of the origin of the selective effects of leptin on BAT. No differences in LEPR expression were observed between BAT, VAT, or PVAT in male and female LEPRloxTB × APN-Cre mice; only SAT exhibited a marked increase in Lepr expression in comparison with BAT in both sexes. Therefore, these data rule out LEPR expression level as an explanation for the tissue specificity. The unique nature of BAT cells, which originate from myogenic factor 5–positive progenitor cells (whereas WAT adipocytes derive from myogenic factor 5–negative progenitor cells [21]) may contribute to the distinct response to leptin. Similarly, activation of different signaling pathways within white and brown adipocytes, as well as the potential development of tissue-specific resistance to leptin, may explain the differences. Based on the very high circulating leptin levels in LEPRloxTB and LEPRloxTB × APN-Cre mice, one can reasonably speculate that BAT remains leptin sensitive, whereas WAT may have developed resistance to leptin. However, addressing these questions is beyond the scope of the current study.

Our study reveals for the first time under in vivo and in pathophysiological conditions a direct role for leptin in the control of BAT function and shows that BAT leptin signaling could increase lipolysis. BAT function is critically reliant on UCP1 expression, which was upregulated after restoration of LEPR expression. Although the precise mechanisms by which adipocyte-specific leptin signaling regulates UCP1 levels remain to be elucidated, our findings suggest several potential pathways that may underlie this regulation. Leptin classically activates STAT3 signaling (10). However, although we report increased BAT STAT3 activation, recent evidence suggests that STAT3 inhibition can paradoxically enhance UCP1 expression in brown adipocytes (22). This likely indicates that other leptin-activated pathways, such as AKT, AMPK, or MAPK, may contribute to the induction of UCP1 and thermogenic genes (23–25). Interestingly, BAT LEPR restoration increased pAKT/AKT, suggesting that this pathway could be involved. Other mediators known to enhance UCP1, such as cAMP and PPARγ, may also contribute to leptin-mediated UCP1 expression, because leptin has been shown to increase PPARγ in endothelial cells and activate cAMP signaling in adipose tissue macrophages (26–28). Because UCP1 exerts its thermogenic function within the inner mitochondrial membrane (29), we also quantified markers of mitochondrial function and abundance. BAT LEPR restoration led to increases in BAT Pgc1α, a master regulator of mitochondrial number, function, and quality (30), as well as TOM20, a marker of mitochondrial content, but without altering the ratio of mtDNA to nuclear DNA. These finding suggests that the enhanced thermogenic phenotype is likely driven primarily by improved mitochondrial function rather than by a substantial increase in mitochondrial abundance. Given the significant induction of UCP1 and PGC1α, it is plausible that leptin signaling promotes mitochondrial activity or remodeling rather than large-scale biogenesis. However, additional studies are required to identify the exact molecular mechanisms whereby leptin controls UCP1 levels and BAT activity.

Our results also imply increased FFA production through increases in HSL activity and BAT vascularization. Indeed, although BAT activity has been positively related to BAT vascular density (16,31), we show that LEPR restoration significantly increased BAT capillary density, as shown by increases in isolectin B4 staining, and endothelial markers, including CD31 and CDH5. Moreover, consistent with the central role of VEGFA in the control of BAT vascularization (16,32), we reported increased levels of Vegfa in LEPRloxTB × APN-Cre mouse BAT. VEGFA is produced by adipocytes in adipose tissue (33). Consistent with the literature (34), we show that restoration of leptin signaling activated the STAT3 pathway in adipocytes, which is known to upregulate VEGFA in retinal endothelial cells (35). Given that adipocytes can produce VEGFA, it is plausible that leptin signaling directly enhances VEGFA expression in BAT adipocytes as well, promoting angiogenesis. In addition, our study shows that other angiogenic factors, including Angpt1, Angpt2, Tgf-β, and Hif1, were also upregulated after adipocyte LEPR restoration. ANGPT2 has been reported to be directly enhanced by leptin in adipocytes (36) and could act synergistically with VEGFA to promote endothelial cell proliferation and vessel maturation (37). TGF-β and HIF-1 further enhance the angiogenic response by stabilizing new capillary networks and adapting BAT to increased metabolic demands, the former of which is related to brown and beige adipocyte differentiation (38–40). These findings suggest that leptin signaling in adipocytes orchestrates a complex angiogenic program beyond VEGFA activation.

Another major finding of our study is that LEPR-mediated BAT remodeling and activation were exclusively observed in males. The higher restoration of LEPR in male mouse BAT compared with female mouse BAT would be the easiest explanation. However, the obesity consecutive to LEPR deficiency did not alter BAT morphology or function in females, and LEPR restoration in male mouse BAT did in fact abolish the sex difference. This supports sex differences in the control of BAT morphology and function and suggests leptin-independent mechanisms in females. The preserved BAT function and morphology in obese females were likely due to estrogen, which drives BAT remodeling and increases energy expenditure through peripheral estrogen receptor-α signaling (41,42). Therefore, it is likely that BAT morphology in females had already been optimized by estrogen, preventing further structural adaptation on adipocyte-specific LEPR restoration.

Added to the enhanced BAT function, adipocyte LEPR restoration markedly improved cardiovascular function in male mice, as reflected by a reduction in BP and arterial stiffness and improved endothelial function. Given the inherent limitations of the tail-cuff technique, including its susceptibility to stress-induced variability, substantial operator dependence, and inability to accurately record diastolic BP or heart rate, the absolute BP values obtained should be interpreted with caution. However, the reduced BP reported is corroborated by consistent changes across multiple independent cardiovascular parameters, collectively supporting a genuine decrease in BP. This improved cardiovascular function was accompanied by lower systemic and tissue inflammation, except for adipose tissue. Sustained hyperglycemia and insulin resistance, as seen in diabetes, are a major cause of cardiovascular complications, including hypertension, atherosclerosis, inflammation, and endothelial dysfunction (43,44). Furthermore, enhanced energy expenditure reduces the risk of cardiovascular diseases via improved insulin sensitivity (45). Therefore, one can reasonably speculate that LEPR-mediated BAT activation alleviates the deleterious effects of hyperglycemia on cardiovascular function by improving insulin sensitivity. BAT typically represents a relatively small fraction of whole-body glucose disposal under physiological conditions. Therefore, additional glucose tracer studies and tissue-specific glucose uptake measurements are required to clarify the precise mechanisms by which insulin sensitivity is primarily improved. In addition to improving glycemia and reducing vascular inflammation, BAT can influence cardiovascular function via the secretion of endocrine factors, such as FGF21 and NRG4, known as cardioprotective batokines (17,18). We observed that adipocyte LEPR restoration increased BAT Fgf21 and Nrg4 transcript levels exclusively in males. Remarkably, females that did not demonstrate improved cardiovascular function with adipocyte LEPR reexpression exhibited no alterations in batokine transcript levels. Although these data are only correlative, they support a potential contribution of batokines to the observed improvements in BP and vascular function in males. Furthermore, these latter data substantiate the concept that BAT leptin signaling controls glycemia and cardiovascular function in males only. Indeed, we report that irrespective of the presence of adipocyte LEPR, obese female mice exhibited no alterations in BAT function or glycemia but surprisingly developed cardiovascular alterations, supporting a lack of association between adipocyte leptin signaling, BAT thermogenic capacity, and cardiovascular health in females. Likely contributing to this male-specific improvement in metabolic and cardiovascular function is the reduced inflammation reported at the systemic level in the blood and cardiovascular organs, including the heart and aorta. However, surprisingly, and in contradiction with the improved systemic inflammation, adipocyte LEPR reexpression did not alter inflammatory marker levels in WAT but instead led to an increase in Tnf-α and F4/80 in male mouse BAT. WAT may be relatively refractory to remodeling of inflammatory gene expression because chronic features of its microenvironment, such as fibrosis, crown-like structures, and long-lived resident macrophages, can sustain local inflammation despite systemic metabolic improvements (46–48). Although counterintuitive and in opposition to previous studies reporting that TNF-α promotes apotosis in BAT (49), our BAT findings are consistent with the observation that deficiency in TNF-α receptors 1 and 2 in mice elevates fat mass and adipose tissue macrophage infiltration and induces insulin resistance (50), whereas increases in circulating TNF-α levels increase energy expenditure (51). In further agreement with these findings, inhibition of TNF-α with etanercept promotes body weight gain in humans (52,53), whereas elevated plasma TNF-α levels are responsible for the high energy expenditure observed in patients with chronic obstructive pulmonary disease and cystic fibrosis (54,55). Lastly, consistent with our angiogenic data, TNF-α has been reported to increase VEGFA and ANGPT2 in preadipocytes in culture (56). Considering the established link between inflammation, angiogenesis, and tissue remodeling in adipose depots (57,58), the increase in BAT inflammation may reflect enhanced vascularization rather than a deleterious process, highlighting the distinct regulatory environment of BAT compared with WAT. Nevertheless, further investigation into how inflammation contributes to BAT activation and leptin signaling in adipose tissue is warranted.

In conclusion, we report for the first time a male-specific role of adipocyte leptin signaling in the regulation of BAT function, particularly in the modulation of BAT lipolysis and vascularization. These processes, in turn, contribute to the regulation of systemic glycolysis and cardiovascular function. Our findings highlight adipocyte leptin signaling as a potential therapeutic target for the treatment of metabolic and cardiovascular disorders in males.

This article contains supplementary material online at https://doi.org/10.2337/figshare.30776363.

Article Information

Acknowledgments. The authors thank the Electron Microscopy & Histology Core Facility, Medical College of Georgia, Augusta University (research resource identifier SCR_026810) for assistance with histological analyses; Jing Zhao, Electron Microscopy & Histology Core, Medical College of Georgia, Augusta University, for hematoxylin-eosin staining and immunostaining and James Mints, Vascular Biology Center, Medical College of Georgia, Augusta University, for help with nuclear magnetic resonance and Comprehensive Lab Animal Monitoring Systems measurements; and FLIR Systems, Inc., for lending the FLIR T540 thermal imaging system used in this study.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. Y.O. was responsible for conceptualization, methodology, formal analysis, data curation, writing of the original manuscript draft, figure preparation, and funding acquisition. S.K., B.T.W., and J.M. were responsible for mouse management and material procurement. E.J.B.d.C. was responsible for conceptualization, data curation, project administration, writing of the original manuscript draft, and funding acquisition. E.J.B.d.C. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding Statement

This work was supported by National Institutes of Health grants R01HL155265, R01AR082307, P01HL1605571, R01HL176323, and R01HL175471 (E.J.B.d.C.) and American Heart Association grant 25POST136864 (Y.O.).

Supporting information

Supplementary Material
db250388_supp.zip (2.6MB, zip)

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Supplementary Material
db250388_supp.zip (2.6MB, zip)

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