Hypothalamic control of body fat mass by food intake: The key to understanding why obesity should be treated as a disease.

BACKGROUND: Hypothalamic centres have been recognized to play a central role in body weight regulation for nearly 70 years. AIMS: In this review, we will explore the current undersanding of the role the hypothalamus plays in controlling food intake behaviours. MATERIALS AND METHODS: Review of relevant literature from PubMed searches and review article citations. RESULTS: Beginning with autopsy studies showing destructive hypothalamic lesions in patients manifesting hyperphagia and rapid weight gain, followed by animal lesioning studies pinpointing adjacent hypothalamic sites as the 'satiety' centre and the 'feeding' centre of the brain, the neurocircuitry that governs our body weight is now understood to consist of a complex, interconnected network, including the hypothalamus and extending to cortical sites, reward centres and brainstem. Neurons in these sites receive afferent signals from the gastrointestinal tract and adipose tissue indicating food availability, calorie content, as well as body fat mass. DISCUSSION: Integration of these complex signals leads to modulation of the two prime effector systems that defend a body fat mass set point: food intake and energy expenditure. CONCLUSION: Understanding the hypothalamic control of food intake forms the foundation for understanding and managing obesity as a chronic disease.

Obesity alters the circadian profiles of energy metabolism and glucose regulation in humans.

OBJECTIVE: Given the complex interaction among the circadian system, energy metabolism, and obesity, the authors tested whether having obesity impacts the circadian variation in energy and glucose metabolism in humans. METHODS: Participants with BMI either in the healthy weight or obesity ranges were studied in a 5-day, in-laboratory protocol that equally distributed behaviors (i.e., sleep, eating, exercise) across 24 h. Energy metabolism was measured at rest and during a standardized exercise bout and blood was sampled before and after each identical study meal to assess glucose and insulin levels. RESULTS: In those with a healthy weight, the circadian nadir of energy expenditure, during both rest and exercise, occurred when participants would normally be asleep. However, in those with obesity, this nadir appears to occur during the habitual wake period. Differences in glucose regulation also depended on the circadian phase, such that individuals with obesity appeared to have relatively greater glucose intolerance during the circadian day and produced less insulin during the circadian night. CONCLUSIONS: Obesity is associated with altered circadian energy and glucose metabolism. Understanding and addressing these associations could lead to strategies that improve body weight and metabolic health in people with obesity.

Metabolite signature of diabetes remission in individuals with obesity undergoing weight loss interventions.

OBJECTIVE: This observational study investigated metabolomic changes in individuals with type 2 diabetes (T2D) after weight loss. We hypothesized that metabolite changes associated with T2D-relevant phenotypes are signatures of improved health. METHODS: Fasting plasma samples from individuals undergoing bariatric surgery (n = 71 Roux-en-Y gastric bypass [RYGB], n = 22 gastric banding), lifestyle intervention (n = 66), or usual care (n = 14) were profiled for 139 metabolites before and 2 years after weight loss. Principal component analysis grouped correlated metabolites into factors. Association of preintervention metabolites was tested with preintervention clinical features and changes in T2D markers. Association between change in metabolites/metabolite factors and change in T2D remission markers, homeostasis model assessment of ß-cell function, homeostasis model assessment of insulin resistance, and glycated hemoglobin (HbA1c) was assessed. RESULTS: Branched-chain amino acids (BCAAs) were associated with preintervention adiposity. Changes in BCAAs (valine, leucine/isoleucine) and branched-chain ketoacids were positively associated with change in HbA1c (false discovery rate q value ≤ 0.001) that persisted after adjustment for percentage weight change and RYGB (p ≤ 0.02). In analyses stratified by RYGB or other weight loss method, some metabolites showed association with non-RYGB weight loss. CONCLUSIONS: This study confirmed known metabolite associations with obesity/T2D and showed an association of BCAAs with HbA1c change after weight loss, independent of the method or magnitude of weight loss.

A low-fat diet improves fatigue in multiple sclerosis: Results from a randomized controlled trial.

BACKGROUND: Fatigue can be a disabling multiple sclerosis (MS) symptom with no effective treatment options. OBJECTIVE: Determine whether a low-fat diet improves fatigue in people with MS (PwMS). METHODS: We conducted a 16-week randomized controlled trial (RCT) and allocated PwMS to a low-fat diet (active, total daily fat calories not exceeding 20%) or wait-list (control) group. Subjects underwent 2 weeks of baseline diet data collection (24-hour diet recalls (24HDRs)), followed by randomization. The active group received 2 weeks of nutrition counseling and underwent a 12-week low-fat diet intervention. One set of three 24HDRs at baseline and week 16 were collected. We administered a food frequency questionnaire (FFQ) and Modified Fatigue Impact Scale (MFIS) every 4 weeks. The control group continued their pre-study diet and received diet training during the study completion. RESULTS: We recruited 39 PwMS (20-active; 19-control). The active group decreased their daily caloric intake by 11% (95% confidence interval (CI): -18.5%, -3.0%) and the mean MFIS by 4.0 (95% CI: -12.0, 4.0) compared to the control (intent-to-treat). Sensitivity analysis strengthened the association with a mean MFIS difference of -13.9 (95% CI: -20.7, -7.2). CONCLUSIONS: We demonstrated a significant reduction in fatigue with a low-fat dietary intervention in PwMS.

Sex differences in the impact of physical frailty on outcomes in heart failure.

BACKGROUND: Physical frailty is strongly related to adverse outcomes in heart failure (HF), and women are more likely to be physically frail than men; however, it is unknown if this sex difference affects outcomes. OBJECTIVES: To determine if there are sex differences in the associations between physical frailty and health-related quality of life (HRQOL) and clinical outcomes in HF. METHODS: We conducted a prospective study of adults with HF. Physical frailty was assessed using the Frailty Phenotype Criteria. HRQOL was assessed using the Minnesota Living with HF Questionnaire. One-year clinical events (all-cause death or cardiovascular hospitalization or emergency department visit) were ascertained. We used generalized linear modeling to quantify associations between physical frailty and HRQOL, and Cox proportional hazards modeling to quantify associations between physical frailty and clinical events, adjusting for Seattle HF Model scores. RESULTS: The sample (n = 115) was 63.5 ± 15.7 years old and 49% women. Physical frailty was associated with significantly worse total HRQOL among women (p = 0.005) but not men (p = 0.141). Physical frailty was associated with worse physical HRQOL among both women (p < 0.001) and men (p = 0.043). There was a 46% higher clinical event risk for every one-point increase in physical frailty score among men (p = 0.047) but not women (p = 0.361). CONCLUSIONS: Physical frailty is associated with worse overall HRQOL among women and higher clinical event risk among men, indicating a need to better understand contributors to sex-specific health differences associated with physical frailty in HF.

What is Obesity?: Definition as a Disease, with Implications for Care.

Advances in the understanding of weight regulation provide the framework for the recognition of obesity as a chronic disease. Lifestyle approaches are foundational in the prevention of obesity and should be continued while weight management interventions, including antiobesity medications and metabolic-bariatric procedures, are offered to eligible patients. Clinical challenges remain, however, including overcoming obesity stigma and bias within the medical community toward medical and surgical approaches, ensuring insurance coverage for obesity management (including medications and surgery), and promoting policies that reverse the upward worldwide trend in obesity and adiposity complications in populations.

Obesity-Associated Dyslipidemia Is Moderated by Habitual Intake of Marine-Derived n-3 Polyunsaturated Fatty Acids in Yup'ik Alaska Native People: A Cross-Sectional Mediation-Moderation Analysis.

BACKGROUND: Obesity leads to insulin resistance, altered lipoprotein metabolism, dyslipidemia, and cardiovascular disease. The relationship between long-term intake of n-3 polyunsaturated fatty acids (n-3 PUFAs) and prevention of cardiometabolic disease remains unresolved. OBJECTIVES: The aim of this study was to explore direct and indirect pathways between adiposity and dyslipidemia, and the degree to which n-3 PUFAs moderate adiposity-induced dyslipidemia in a population with highly variable n-3 PUFA intake from marine foods. METHODS: In total, 571 Yup'ik Alaska Native adults (18-87 y) were enrolled in this cross-sectional study. The red blood cell (RBC) nitrogen isotope ratio (15N/14N, or NIR) was used as a validated objective measure of n-3 PUFA intake. EPA and DHA were measured in RBCs. Insulin sensitivity and resistance were estimated by the HOMA2 method. Mediation analysis was conducted to evaluate the contribution of the indirect causal path between adiposity and dyslipidemia mediated through insulin resistance. Moderation analysis was used to assess the influence of dietary n-3 PUFAs on the direct and indirect paths between adiposity and dyslipidemia. Outcomes of primary interest included plasma total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), non-HDL-C, and triglycerides (TG). RESULTS: In this Yup'ik study population, we found that up to 21.6% of the total effects of adiposity on plasma TG, HDL-C, and non-HDL-C are mediated through measures of insulin resistance or sensitivity. Moreover, RBC DHA and EPA moderated the positive association between waist circumference (WC) and TC or non-HDL-C, whereas only DHA moderated the positive association between WC and TG. However, the indirect path between WC and plasma lipids was not significantly moderated by dietary n-3 PUFAs. CONCLUSIONS: Intake of n-3 PUFAs may independently reduce dyslipidemia through the direct path resulting from excess adiposity in Yup'ik adults. NIR moderation effects suggest that additional nutrients contained in n-3 PUFA-rich foods may also reduce dyslipidemia.

Self-selected meal composition alters the relationship between same-day caloric intake and appetite scores in humans during a long-term ad-libitum feeding study.

PURPOSE: To determine the effect of an off-protocol meal during a long-term ad libitum feeding study on changes in total caloric consumption and ratings of hunger and satiety. METHODS: During the ad libitum portion of a 16 weeks research high-protein feeding study, 19 participants were allowed to eat up to one self-selected meal (SSM) a week instead of an intervention diet meal. The SSM was assessed for total caloric and macronutrient composition and compared to the intervention diet for 3 days before and after the SSM day. Visual analog scores rating daily hunger and fullness were collected and compared as well. RESULTS: On the SSM day, the mean ± SD daily caloric intake increased by 262 ± 332 kcal compared to the previous study days (P < 0.001), with no changes in subjective appetite scores. The following day there was a slight but significant reduction in intake (- 58 ± 85 kcal, P = 0.008) compared to the average pre-SSM day with no change in appetite scores. On the SSM day, percent protein intake was inversely associated mean daily caloric intake (r2 = 0.22, P = 0.03). CONCLUSIONS: During a long-term, ad-libitum high-protein feeding study, one SSM lower in protein increased daily total caloric consumption with no impact on appetite ratings and incomplete caloric consumption during subsequent days. These data suggest that during ad-libitum feeding, a single meal change in protein content impacts the relationships between daily level of hunger, satiety and calorie intake. GOV ID: NCT05002491 (retrospectively registered 07/20/2021).

Candidate biomarkers of physical frailty in heart failure: an exploratory cross-sectional study.

AIMS: Physical frailty is highly prevalent and predictive of worse outcomes in heart failure (HF). Candidate biomarker analysis may help in understanding the mechanisms underlying physical frailty in HF. We aimed to identify candidate biomarkers associated with physical frailty in HF using a multimarker strategy of distinct pathophysiological processes. METHODS AND RESULTS: We collected data and plasma samples from 113 adults with New York Heart Association Functional Class I-IV HF. Physical frailty was measured with the Frailty Phenotype Criteria. Plasma biomarkers included: N-terminal pro-B-type natriuretic peptide, norepinephrine, dihydroxyphenylglycol, soluble tumour necrosis factor alpha receptor-1, adiponectin, insulin, glucose, insulin-like growth factor-1 (IGF-1), and myostatin. Comparative statistics and multivariate linear regression were used to test group differences and associations. The average age was 63.5 ± 15.7 years, half were women (48%), and most had a non-ischaemic aetiology of HF (73%). Physical frailty was identified in 42% and associated with female sex, higher body mass index and percent body fat, more comorbidities, and HF with preserved ejection fraction. Adjusting for Seattle HF Model projected survival score, comorbidities, body composition, and sex, physical frailty was associated with significantly lower plasma adiponectin [ß ± standard error (SE) -0.28 ± 0.14, P = 0.047], IGF-1 (ß ± SE -0.21 ± 0.10, P = 0.032), and myostatin (ß ± SE -0.22 ± 0.09, P = 0.011). In sex-stratified analyses, IGF-1 and myostatin were significantly associated with physical frailty in men but not women. CONCLUSION: We identified biomarkers involved in adipose tissue and skeletal muscle development, maintenance, and function that were associated with physical frailty in HF.

Obstacles and opportunities in managing coexisting obesity and CKD: Report of a scientific workshop cosponsored by the National Kidney Foundation and The Obesity Society.

The National Kidney Foundation (NKF) and The Obesity Society (TOS) cosponsored a multispecialty international workshop in April 2021 to advance the understanding and management of obesity in adults with chronic kidney disease (CKD). The underlying rationale for the workshop was the accumulating evidence that obesity is a major contributor to CKD and adverse outcomes in individuals with CKD, and that effective treatment of obesity, including lifestyle intervention, weight loss medications, and metabolic surgery, can have beneficial effects. The attendees included a range of experts in the areas of kidney disease, obesity medicine, endocrinology, diabetes, bariatric/metabolic surgery, endoscopy, transplant surgery, and nutrition, as well as patients with obesity and CKD. The group identified strategies to increase patient and provider engagement in obesity management, outlined a collaborative action plan to engage nephrologists and obesity medicine experts in obesity management, and identified research opportunities to address gaps in knowledge about the interaction between obesity and kidney disease. The workshop's conclusions help lay the groundwork for development of an effective, scientifically based, and multidisciplinary approach to the management of obesity in people with CKD.

Obstacles and Opportunities in Managing Coexisting Obesity and CKD: Report of a Scientific Workshop Cosponsored by the National Kidney Foundation and The Obesity Society.

The National Kidney Foundation (NKF) and The Obesity Society (TOS) cosponsored a multispecialty international workshop in April 2021 to advance the understanding and management of obesity in adults with chronic kidney disease (CKD). The underlying rationale for the workshop was the accumulating evidence that obesity is a major contributor to CKD and adverse outcomes in individuals with CKD, and that effective treatment of obesity, including lifestyle intervention, weight loss medications, and metabolic surgery, can have beneficial effects. The attendees included a range of experts in the areas of kidney disease, obesity medicine, endocrinology, diabetes, bariatric/metabolic surgery, endoscopy, transplant surgery, and nutrition, as well as patients with obesity and CKD. The group identified strategies to increase patient and provider engagement in obesity management, outlined a collaborative action plan to engage nephrologists and obesity medicine experts in obesity management, and identified research opportunities to address gaps in knowledge about the interaction between obesity and kidney disease. The workshop's conclusions help lay the groundwork for development of an effective, scientifically based, and multidisciplinary approach to the management of obesity in people with CKD.

Weight gain trajectories and obesity rates in intensive and conventional treatments of type 1 diabetes from the DCCT compared with a control population without diabetes.

AIM: Obesity is a significant health issue for participants with type 1 diabetes undergoing intensive diabetes management. The temporal pattern and factors associated with weight gain after treatment initiation remain poorly understood including how weight gain in participants with and without type I diabetes compare. Our aim was to compare weight gain in those receiving intensive (INT) and conventional (CONV) type 1 diabetes treatment to a population without diabetes. METHODS: Participants included men and women of 18 years and older in the Diabetes Control and Complications Trial (DCCT) randomized to INT (n = 562) or CONV (n = 568) and a prospective, observational cohort without diabetes from the Coronary Artery Development in Young Adults (CARDIA, controls) study (n = 2446). Body mass index (BMI) trajectories and obesity prevalence were compared between groups and candidate metabolic and therapeutic moderators investigated. RESULTS: Annual weight gain with INT peaked 1.3 years after initiation and was greater than both CONV and controls before and after this peak. Obesity prevalence with INT was lower than controls at baseline, was similar to controls at 2 years and surpassed controls by 5 years. Obesity rates with CONV remained below controls at all time points. Greater annual weight gain in the DCCT was associated with lower haemoglobin A1c , higher insulin dose and family history of type 2 diabetes. CONCLUSIONS: Greater weight gain accompanying INT therapy occurs in two stages, leads to similar or greater obesity rates than controls after 2 years and is primarily modified by glucose control and family history, supportive of a therapeutic-genetic influence on weight trajectories.

Changes in Visceral and Ectopic Adipose Tissue Stores Across Pregnancy and Their Relationship to Gestational Weight Gain.

BACKGROUND: Excessive gestational weight gain has been associated with increased total body fat (TBF), metabolic syndrome, and abdominal obesity. However, little is known about the relationship of gestational weight gain with changes in metabolically active visceral or ectopic (hepatic and skeletal muscle) lipid stores. OBJECTIVES: In a prospective study of 50 healthy, pregnant women, we assessed whether changes in weight were associated with changes in total, visceral, and ectopic lipid stores. METHODS: Participants (ages 19-39) were primarily White (84%). The mean preconception BMI was 25.8 kg/m2 (SD, 4.5 kg/m2; min-max, 17.1-35.9 kg/m2). Measurements were completed at visits 1 and 2 at means of 16 and 34 weeks gestation, respectively, and included TBF using BOD POD; abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) using MRI; and intrahepatic lipids (IHL), intramyocellular lipids (IMCL), and extramyocellular lipids (EMCL) using magnetic resonance spectroscopy. We used paired t-tests to examine changes in adipose tissue and Pearson's correlation to examine associations of adipose tissue changes and weight changes. We also examined whether changes in adipose tissue stores differed by preconception BMI (normal, overweight, and obese), using 1-way ANOVA. RESULTS: The TBF (mean change, +3.5 kg; 95% CI: 2.4-4.6 kg), SAT (mean change, +701 cm3; 95% CI: 421-981 cm3), VAT (mean change, +275 cm3; 95% CI: 170-379 cm3), and IHL (percentage water peak; median, +0.15; IQR = -0.01 to 0.32) values increased significantly; the IMCL and EMCL values did not change. Changes varied by BMI strata, with the least increase (or, for SAT, net loss) among women with obesity. Weight change was positively correlated with changes in TBF (r = 0.83; P < 0.001), SAT (r = 0.74; P < 0.001), and VAT (r = 0.63; P < 0.001) but not significantly correlated with changes in ectopic lipids (IHL, IMCL, and EMCL; -0.14 < r < 0.26). CONCLUSIONS: Preferential deposition of adipose tissue to the viscera in pregnancy, as seen in our sample, could serve an important metabolic function; however, excessive deposition in this region could negatively affect maternal health.

Habitual Intake of Marine-Derived n-3 PUFAs is Inversely Associated with a Cardiometabolic Inflammatory Profile in Yup'ik Alaska Native People.

BACKGROUND: The relationship between dietary n-3 PUFAs and the prevention of cardiometabolic diseases, including type 2 diabetes, is unresolved. Examination of the association between n-3 PUFAs and chronic low-grade inflammation in a population where many individuals have had an extremely high intake of marine mammals and fish throughout their lifespan may provide important clues regarding the impact of n-3 PUFAs on health. OBJECTIVES: The aim of this study was to explore associations between concentrations of n-3 PUFAs resulting from habitual intake of natural food sources high in fish and marine mammals with immune biomarkers of metabolic inflammation and parameters of glucose regulation. METHODS: A total of 569 Yup'ik Alaska Native adults (18-87 years old) were enrolled in this cross-sectional study between December 2016 and November 2019. The RBC nitrogen isotope ratio (NIR; 15N/14N) was used as a validated measure of n-3 PUFA intake to select 165 participant samples from the first and fourth quartiles of n-3 PUFA intakes. Outcomes included 38 pro- and anti-inflammatory cytokines and 8 measures of glucose homeostasis associated with type 2 diabetes risks. These outcomes were evaluated for their associations with direct measurements of EPA, DHA, and arachidonic acid in RBCs. ANALYSIS: Linear regression was used to detect significant relationships with cytokines and n-3 PUFAs, adiposity, and glucose-related variables. RESULTS: The DHA concentration in RBC membranes was inversely associated with IL-6 (ß = -0.0066; P < 0.001); EPA was inversely associated with TNFα (ß = -0.4925; P < 0.001); and the NIR was inversely associated with Monocyte chemoattractant protein-1 (MCP-1) (ß = -0.8345; P < 0.001) and IL-10 (ß = -1.2868; P < 0.001). CONCLUSIONS: Habitual intake of marine mammals and fish rich in n-3 PUFAs in this study population of Yup'ik Alaska Native adults is associated with reduced systemic inflammation, which may contribute to the low prevalence of diseases in which inflammation plays an important role.

Real-world utilization of bempedoic acid in an academic preventive cardiology practice.

BACKGROUND: Lipid management for prevention and treatment of cardiovascular disease remains insufficient for many with currently available therapies. OBJECTIVE: Evaluate real-world use of bempedoic acid. METHODS: Retrospective study of patients in our Center for Preventive Cardiology who were prescribed bempedoic acid between February 2020 and July 2021. Patients were managed according to clinical standards of care, with lipid assessments at months ≤3, 6, and 12 post-bempedoic acid initiation. RESULTS: Seventy-three patients were prescribed bempedoic acid, with 64 initiating therapy. The majority had atherosclerosis (89%), familial hypercholesterolemia (64%), and statin intolerance (74%), with baseline low-density lipoprotein cholesterol (LDL-C) 120 mg/dL. Prior authorization requests and appeals of denials were required in 90% and 19% of cases, respectively. Cost-mitigating strategies reduced median monthly drug costs from $432 pre-insurance approval to $80 post-insurance approval, to $10 after financial assistance intervention. Bempedoic acid reduced LDL-C by -36.7%, -31%, and -20.3% at ≤3, 6, and 12, respectively, with >20% achieving LDL-C <70 mg/dL. There was substantial inter-individual heterogeneity in LDL-C lowering. We observed high rates of drug discontinuation (35.9%), mostly related to treatment-emergent adverse events (TEAEs) (32.8%), primarily musculoskeletal complaints. Use of reduced dose bempedoic acid (<180 mg) was associated similar LDL-C lowering but TEAE and drug discontinuation were still common. CONCLUSIONS: Real-world use of bempedoic acid was limited by insurance and cost barriers requiring substantial post-prescription interventions. In patients at heightened risk for atherosclerotic events and statin intolerance, bempedoic acid was associated with clinically meaningful LDL-C lowering, but high rates of TEAEs and drug discontinuations.

The importance of nutrition in pregnancy and lactation: lifelong consequences.

Most women in the United States do not meet the recommendations for healthful nutrition and weight before and during pregnancy. Women and providers often ask what a healthy diet for a pregnant woman should look like. The message should be "eat better, not more." This can be achieved by basing diet on a variety of nutrient-dense, whole foods, including fruits, vegetables, legumes, whole grains, healthy fats with omega-3 fatty acids that include nuts and seeds, and fish, in place of poorer quality highly processed foods. Such a diet embodies nutritional density and is less likely to be accompanied by excessive energy intake than the standard American diet consisting of increased intakes of processed foods, fatty red meat, and sweetened foods and beverages. Women who report "prudent" or "health-conscious" eating patterns before and/or during pregnancy may have fewer pregnancy complications and adverse child health outcomes. Comprehensive nutritional supplementation (multiple micronutrients plus balanced protein energy) among women with inadequate nutrition has been associated with improved birth outcomes, including decreased rates of low birthweight. A diet that severely restricts any macronutrient class should be avoided, specifically the ketogenic diet that lacks carbohydrates, the Paleo diet because of dairy restriction, and any diet characterized by excess saturated fats. User-friendly tools to facilitate a quick evaluation of dietary patterns with clear guidance on how to address dietary inadequacies and embedded support from trained healthcare providers are urgently needed. Recent evidence has shown that although excessive gestational weight gain predicts adverse perinatal outcomes among women with normal weight, the degree of prepregnancy obesity predicts adverse perinatal outcomes to a greater degree than gestational weight gain among women with obesity. Furthermore, low body mass index and insufficient gestational weight gain are associated with poor perinatal outcomes. Observational data have shown that first-trimester gain is the strongest predictor of adverse outcomes. Interventions beginning in early pregnancy or preconception are needed to prevent downstream complications for mothers and their children. For neonates, human milk provides personalized nutrition and is associated with short- and long-term health benefits for infants and mothers. Eating a healthy diet is a way for lactating mothers to support optimal health for themselves and their infants.

Pregnancy and weaning regulate human maternal liver size and function.

During pregnancy, the rodent liver undergoes hepatocyte proliferation and increases in size, followed by weaning-induced involution via hepatocyte cell death and stromal remodeling, creating a prometastatic niche. These data suggest a mechanism for increased liver metastasis in breast cancer patients with recent childbirth. It is unknown whether the human liver changes in size and function during pregnancy and weaning. In this study, abdominal imaging was obtained in healthy women at early and late pregnancy and postwean. During pregnancy time points, glucose production and utilization and circulating bile acids were measured. Independently of weight gain, most women's livers increased in size with pregnancy, then returned to baseline postwean. Putative roles for bile acids in liver growth and regression were observed. Together, the data support the hypothesis that the human liver is regulated by reproductive state with growth during pregnancy and volume loss postwean. These findings have implications for sex-specific liver diseases and for breast cancer outcomes.