Biology subjects

Wall, B. T.

Publications and source records attributed to Wall, B. T..

2 recordsLinked to original sources

bioRxiv2025

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

While leptin control of metabolism 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 KO 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 cell and angiogenesis in male 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 pro-inflammatory cytokines and reduced tissue inflammation in the aorta and the 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 HighlightsLeptin is known to enhance 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, remain ill-defined. We addressed this question by selectively restoring leptin receptor (LEPR) in adipocytes of obese LEPR conditional KO mice. LEPR restoration selectively enhanced BAT activity in male mice, which led to improved glycemic control and cardiovascular function. These findings revealed a crucial role for BAT leptin signaling in regulating energy expenditure, glycemic and cardiovascular health, primarily in males. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/681380v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@ed0b30org.highwire.dtl.DTLVardef@79ba56org.highwire.dtl.DTLVardef@1b86d93org.highwire.dtl.DTLVardef@1220a46_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2023

The impact of short-term forearm immobilization and acipimox administration on muscle amino acid metabolism and insulin sensitivity in healthy, young volunteers

The mechanisms underpinning short-term muscle disuse atrophy remain to be elucidated, but perturbations in lipid metabolism may be involved. Specifically, positive muscle non-esterified fatty acid (NEFA) balance has been implicated in the development of disuse-induced insulin and anabolic resistance. Our aim was to determine the impact of acipimox administration (i.e. pharmacologically lowering circulating NEFA availability) on muscle amino acid metabolism and insulin sensitivity during short-term disuse. Eighteen healthy individuals (age 22{+/-}1 years, BMI 24.0{+/-}0.6 kg{middle dot}m-2) underwent 2 days of forearm cast immobilization with placebo (PLA; n=9, 5M/4F) or acipimox (ACI; 250 mg Olbetam; n=9, 4M/5F) ingestion four times daily. Before and after immobilization, whole-body glucose disposal rate (GDR), forearm glucose uptake (FGU, i.e. muscle insulin sensitivity), and amino acid kinetics were measured under fasting and hyperinsulinaemic-hyperaminoacidaemic-euglycaemic clamp conditions using arteriovenous forearm balance and intravenous L-[ring-2H5]phenylalanine infusions. Immobilization did not affect GDR but decreased insulin-stimulated FGU in both groups, but to a greater degree in ACI (from 53{+/-}8 to 12{+/-}5 {micro}mol{middle dot}min-1) than in PLA (from 52{+/-}8 to 38{+/-}13 {micro}mol{middle dot}min- 1; P<0.05). In ACI only, fasting arterialised NEFA concentrations were elevated to 1.3{+/-}0.1 mmol{middle dot}L-1 post-immobilization (P<0.05), and fasting forearm NEFA balance increased [~]4-fold (P=0.10). Forearm phenylalanine net balance tended to decrease following immobilization (P<0.10), driven by increases in phenylalanine rates of appearance (from 32{+/-}5 (fasting) and 21{+/-}4 (clamp) pre-immobilization to 53{+/-}8 and 31{+/-}4 post-immobilization; P<0.05) while rates of disappearance were unaffected and no effects of acipimox observed. Altogether, we show disuse-induced insulin resistance is accompanied by early signs of negative net muscle amino acid balance, which is driven by accelerated muscle amino acid efflux. Acutely elevated NEFA availability worsened muscle insulin resistance without affecting muscle amino acid kinetics, suggesting that disuse-associated increased muscle NEFA uptake may contribute to inactivity-induced insulin resistance but does not represent an early mechanism causing anabolic resistance.

physiology↗