Kristin I. Stanford

Purpose of the Review: This review summarizes obesity-induced adaptations in subcutaneous and visceral white adipose tissue (WAT) depots and discusses how incretin-based pharmacotherapies and bariatric surgery may influence WAT remodeling beyond weight loss, drawing on evidence from animal models and human studies. Recent Findings: In obesity, adipose tissue undergoes pathological remodeling characterized by structural and cellular changes, extracellular matrix (ECM) remodeling, altered endocrine signaling, and impaired mitochondrial function that contribute to metabolic comorbidities. Weight-loss interventions, including incretin-based therapies and bariatric surgery, are associated with improvements in adiposity and metabolic outcomes, and multiple studies suggest accompanying changes in inflammatory, mitochondrial/thermogenic, and endocrine pathways within WAT; however, mechanistic evidence in humans remains heterogeneous and is often limited by tissue accessibility and study design. Summary: This review highlights candidate cellular and molecular mechanisms through which incretin-based pharmacotherapies and bariatric surgery may modulate WAT plasticity, emphasizing convergent and distinct effects across depots and the need for more longitudinal, tissue-level human studies to define weight-dependent remodeling versus changes not fully explained by weight loss.

Sphingosine-1-phosphate (S1P) signaling has emerged as a regulator of metabolic homeostasis, but its relationship to brown adipose tissue (BAT) adaptation across physiological conditions remains unclear. We examined how S1P-related gene expression in BAT and subcutaneous white adipose tissue (scWAT) varies with acute exercise, chronic exercise, ambient temperature, aging, sex, and UCP1 deficiency. Young and aged wild-type mice, as well as aged UCP1 knockout (UCP1KO) mice, were studied across acute or chronic exercise paradigms and thermal conditions ranging from 4 °C to 30 °C. In BAT, acute exercise was associated with lower S1pr1, S1pr2, and Sphk1 expression in young females, whereas aged males showed lower S1pr2 and Sphk1 after exercise. In scWAT, exercise-associated induction of S1P-related transcripts was most evident in aged males. Female BAT also displayed broader temperature- and chronic exercise-associated differences in S1pr2, Sphk1, and β-adrenergic receptor transcripts, whereas male BAT showed fewer transcriptional changes. In UCP1KO mice, these exercise-associated patterns were altered or attenuated. Together, these findings identify a context-dependent adipose S1P-related transcriptional program that differs by sex, age, depot, ambient temperature, exercise condition, and UCP1 status.

Severe burn injuries affecting more than 40% of the total body surface area (TBSA) are associated with a high risk of mortality. Clinically, burn injury is

Brown adipose tissue (BAT) is a thermogenic tissue that functions in an endocrine, paracrine, and autocrine manner. BAT secretes extracellular vesicles (EVs) that carry miRNA and proteins involved in mitochondrial function, lipid metabolism, and the β‐oxidation pathway. EVs are small lipid membrane‐bound structures that are secreted by all eukaryotic cells for various purposes like cell signaling, organ crosstalk, and discarding of waste materials. Because EV populations reflect the unique molecular composition, physiological state, and functional roles of the tissues from which they originate, and therefore exhibit substantial heterogeneity across organs, it is essential for mechanistic and therapeutic studies to use an organ‐specific EV isolation method to ensure that the isolated vesicles accurately represent the biology of the source tissue. However, the literature surrounding BAT‐EVs lacks a uniform method for their isolation, with major drawbacks being inconsistent incubation time with ECM‐degrading enzymes and varied media additives. To address this, we systematically subjected mouse BAT to temporal explant culture with dose‐dependent digestion by collagenase type 1 and optimized a protocol to consistently and reproducibly isolate EVs from the BAT‐secretome using size‐exclusion chromatography. This study presents a standardized, efficient, and accessible method with optimized digestion duration and collagenase type 1 concentration to achieve an appropriate yield of BAT‐derived extracellular vesicles (BAT‐EVs).

Maternal physical activity enhances offspring metabolic resilience, whereas prenatal psychosocial stress predisposes offspring to lifelong metabolic dysfunction. Whether maternal exercise can attenuate the deleterious programming effects of stress has remained unclear. Here, we investigated the effect of maternal exercise and/or prenatal psychosocial stress on the metabolic health of male and female offspring. C57BL/6 dams were assigned to four conditions: sedentary/non‐stressed (SED‐NS), sedentary/stressed (SED‐S), exercised/non‐stressed (EX‐NS), or exercised/stressed (EX‐S). Male EX‐NS offspring had improved glucose tolerance compared to SED‐NS and SED‐S; however these effects were blunted in male EX‐S offspring, indicating that prenatal stress abolished this exercise‐induced benefit. In contrast, there was no effect of maternal stress or exercise on glucose tolerance in female offspring. Maternal exercise chronically elevated basal corticosterone in male offspring, regardless of maternal stress. Maternal stress increased mineralocorticoid receptor ( Nr3c2 ) mRNA and glucocorticoid receptor (NR3C1) protein expression in brown adipose tissue in male mice, while exercise restored NR3C1 expression. These findings indicate that prenatal stress blunts the metabolic benefits of maternal exercise in male offspring and is associated with altered corticosteroid signaling in brown adipose tissue. Together, the data identify a stress–exercise interaction that may influence offspring metabolic programming through tissue‐specific regulation of glucocorticoid pathways.

Epidemiological data link a lack of breastfeeding with an increased risk of breast cancer. Breast tissue remodels after pregnancy through involution. Long-term breastfeeding results in gradual involution (GI), and a lack of breastfeeding leads to abrupt involution (AI). AI causes increased mammary gland estrogen signaling, causing adipocyte redifferentiation through neutrophil infiltration. Adipocyte differences and metabolic implications of involution have not been explored between AI and GI. As breast cancer is characterized as highly metabolic, we explored how adipocyte differences and metabolism during involution may support breast cancer risk. FVB/n was randomized to AI/GI and standardized to 6 pups on day 0/birth. AI mice had pups removed on day 7. GI mice had 3 pups removed on days 28 and 31. Mammary glands were harvested at 28, 56, and 120 days. A subset of AI mice were given tamoxifen for 21 days. Day 28 AI glands had upregulation of estrogen signaling, neutrophil degranulation, and glucose metabolism and downregulation of adipogenesis and glycolysis compared to Day 56 GI. Day 120 AI glands had downregulation of oxidative phosphorylation and upregulation of mitochondrial dysfunction similar to estrogen receptor-negative (ER−) pregnancy-associated breast cancer (PABC). AI with tamoxifen resulted in a similar metabolic phenotype to GI. Early metabolic phenotypes in AI and GI glands may be related to estrogen signaling. AI long-term transcriptional metabolic effects were similar to breast cancer.

The role of physical activity and exercise training in preventing the development of chronic disease and reducing mortality is increasingly recognized. A substantial body of evidence indicates that exercise confers these benefits to subsequent generations. This Review examines the effects of parental exercise, focusing on findings published within the past 10 years and related to mechanisms of transmission and sex-specific differences in both parents and offspring. Epigenetic modifications, including DNA methylation, histone modification and small non-coding RNAs, are crucial in how parental exercise influences offspring development. Paternal exercise alters the small RNA pool and methylation profiles in sperm, whereas maternal exercise affects both the in utero environment and postnatal lactation factors. Notably, male offspring show enhanced metabolic benefits, whereas female offspring exhibit greater cardiac improvements than male offspring. These findings highlight the sex-dependent nature of the generational effects of exercise and emphasize the need for further research into the molecular underpinnings and long-term implications for both male and female offspring.

Aging poses significant challenges to cardiovascular health necessitating novel therapeutic approaches. This study investigates the potential of the brown adipose tissue (BAT) derived lipokine 12,13-diHOME to mitigate age-induced impairments in cardiovascular function. Analysis of human and rodent plasma signaling lipids reveals a decline in 12,13-diHOME levels with age. Transplantation of BAT or sustained upregulation of 12,13-diHOME effectively preserved cardiac function in aged male and female mice. Bulk RNA-Seq of hearts from aged mice reveals significant increases in pathways involved in ER stress and fibrosis which were partially attenuated by BAT transplantation or sustained upregulation of 12,13-diHOME. Mechanistically, in vivo and in vitro models demonstrate that 12,13-diHOME alleviated ER stress through CaMKII inhibition, particularly in males. These findings underscore 12,13-diHOME as a promising candidate for combating age-related cardiovascular dysfunction, offering insights into potential therapeutic strategies for addressing cardiovascular diseases in aging populations.

Obesity is increasing rapidly worldwide and is projected to affect approximately half the US population by the year 2035. Obesity is a complex condition, and individuals who have obesity are at greater risk for developing associated metabolic diseases such as type 2 diabetes (T2D), metabolic dysfunction–associated steatohepatitis (MASH), and cardiovascular diseases (CVD). Understanding the underlying factors which contribute to obesity and that impact key molecular mechanisms of metabolic organs such as adipose tissue, liver, and muscle is crucial for combating the disease. Exercise is a well-established measure to prevent or mitigate the adverse consequences of obesity, with several beneficial effects to whole-body metabolism and adaptations to metabolic tissues. This review explores the impact of obesity on the development of metabolic diseases. Specifically, we will discuss: how obesity alters metabolic function and the potential benefits of exercise; the specific effects of obesity and exercise on muscle, adipose tissue, and liver; and potential effects of pharmacotherapeutics or bariatric surgery in combination with exercise.