Incretin-based weight loss pharmacotherapy: Can resistance exercise optimize changes in body composition?

Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR–GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of β-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and β-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and β-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.

ObjectiveOur primary objective was to determine the long-term effects of physical activity (PA) and weight loss (WL) on body composition in overweight/obese older adults. Secondarily, we evaluated the association between change in body mass and composition on change in several cardiometabolic risk factors and mobility.Design and Methods288 older (X±SD: 67.0±4.8 years), overweight/obese (BMI 32.8±3.8 kg/m2) men and women participated in this 18 month randomized, controlled trial. Treatment groups included PA+WL (n=98), PA-only (n=97), and a successful aging (SA) health education control (n=93). DXA-acquired body composition measures (total body fat and lean mass), conventional biomarkers of cardiometabolic risk, and 400-m walk time were obtained at baseline and 18 months.ResultsFat mass was significantly reduced from (X±SE) 36.5±8.9 kg to 31.7±9.0 kg in the PA+WL group (p<0.01), but remained unchanged from baseline in the PA-only (−0.8±3.8 kg) and SA (−0.0±3.9 kg) groups. Lean mass losses were three times greater in the PA+WL group compared to PA-only or SA groups (−2.5±2.8 kg vs. −0.7±2.2 kg or −0.8±2.4 kg, respectively; p<0.01); yet due to a larger decrease in fat mass, percent lean mass was significantly increased over baseline in the PA+WL group (2.1%±2.6%; p<0.01). Fat mass loss was primarily responsible for WL-associated improvements in cardiometabolic risk factors, while reduction in body weight, regardless of compartment, was significantly associated with improved mobility.ConclusionThis 18 month PA+WL program resulted in a significant reduction in percent body fat with a concomitant increase in percent body lean mass. Shifts in body weight and composition were associated with favorable changes in clinical parameters of cardiometabolic risk and mobility. Moderate PA without WL had no effect on body composition.

In Covid-19, variations in fasting blood glucose are considered a distinct risk element for a bad prognosis and outcome in Covid-19 patients. Tirazepatide (TZT), a dual glucagon-like peptide-1 (GLP-1)and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist may be effective in managing Covid-19-induced hyperglycemia in diabetic and non-diabetic patients. The beneficial effect of TZT in T2DM and obesity is related to direct activation of GIP and GLP-1 receptors with subsequent improvement of insulin sensitivity and reduction of body weight. TZT improves endothelial dysfunction (ED) and associated inflammatory changes through modulation of glucose homeostasis, insulin sensitivity, and pro-inflammatory biomarkers release. TZT, through activation of the GLP-1 receptor, may produce beneficial effects against Covid-19 severity since GLP-1 receptor agonists (GLP-1RAs) have anti-inflammatory and pulmoprotective implications in Covid-19. Therefore, GLP-1RAs could effectively treat severely affected Covid-19 diabetic and non-diabetic patients. Notably, using GLP-1RAs in T2DM patients prevents glucose variability, a common finding in Covid-19 patients. Therefore, GLP-1RAs like TZT could be a therapeutic strategy in T2DM patients with Covid-19 to prevent glucose variability-induced complications. In Covid-19, the inflammatory signaling pathways are highly activated, resulting in hyperinflammation. GLP-1RAs reduce inflammatory biomarkers like IL-6, CRP, and ferritin in Covid-19 patients. Therefore, GLP-1RAs like TZ may be effective in Covid-19 patients by reducing the inflammatory burden. The anti-obesogenic effect of TZT may reduce Covid-19 severity by ameliorating body weight and adiposity. Furthermore, Covid-19 may induce substantial alterations in gut microbiota. GLP-1RA preserves gut microbiota and prevents intestinal dysbiosis. Herein, TZT, like other GLP-1RA, may attenuate Covid-19-induced gut microbiota alterations and, by this mechanism, may mitigate intestinal inflammation and systemic complications in Covid-19 patients with either T2DM or obesity. As opposed to that, glucose-dependent insulinotropic polypeptide (GIP) was reduced in obese and T2DM patients. However, activation of GIP-1R by TZT in T2DM patients improves glucose homeostasis. Thus, TZT, through activation of both GIP and GLP-1, may reduce obesity-mediated inflammation. In Covid-19, GIP response to the meal is impaired, leading to postprandial hyperglycemia and abnormal glucose homeostasis. Therefore, using TZT in severely affected Covid-19 patients may prevent the development of glucose variability and hyperglycemia-induced oxidative stress. Moreover, exaggerated inflammatory disorders in Covid-19 due to the release of pro-inflammatory cytokines like IL-1β, IL-6, and TNF-α may lead to systemic inflammation and cytokine storm development. Besides, GIP-1 inhibits expression of IL-1β, IL-6, MCP-1, chemokines and TNF-α. Therefore, using GIP-1RA like TZT may inhibit the onset of inflammatory disorders in severely affected Covid-19 patients. In conclusion, TZT, through activation of GLP-1 and GIP receptors, may prevent SARS-CoV-2-induced hyperinflammation and glucose variability in diabetic and non-diabetic patients.

Introduction. The global prevalence of obesity has increased markedly in recent decades, becoming a major contributor to metabolic syndrome (MetS), cardiovascular disease, and mortality. This trend increasingly affects older adults, in whom obesity often coexists with sarcopenia, frailty, and multimorbidity. Novel pharmacological therapies, particularly glucagon-like peptide-1 (GLP-1) receptor agonists and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, have demonstrated unprecedented efficacy in weight reduction, yet data in geriatric populations remain limited. Materials and Methods. A systematic literature search of PubMed, Embase, and Scopus was conducted for studies published between 2020 and 2025. Results. Both semaglutide and tirzepatide produced substantial and sustained weight loss, with mean reductions ranging from approximately 15% to over 20%, and significant improvements in glycemic control, lipid profile, and blood pressure. Tirzepatide consistently achieved greater weight reduction than semaglutide. Limited subgroup and post hoc analyses suggest that older adults experience meaningful metabolic benefits, although higher rates of gastrointestinal adverse events and treatment discontinuation have been reported. Discussion. In older patients, pharmacologically induced weight loss may be accompanied by disproportionate loss of lean body mass, increasing the risk of sarcopenia, frailty, and functional decline. Without appropriate nutritional and exercise interventions, these risks may attenuate the cardiometabolic benefits of treatment. Conclusions. GLP-1 and dual GLP-1/GIP receptor agonists are highly effective therapies for obesity, including in older adults, but require individualized risk–benefit assessment. Integration with nutritional support and resistance training is essential.

Obesity is a chronic disease associated with increased risk of multiple metabolic and mental health-related comorbidities. Recent advances in obesity pharmacotherapy, particularly with glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), have the potential to transform obesity and type 2 diabetes mellitus (T2DM) care by promoting marked weight loss, improving glycaemic control and addressing multiple obesity-related comorbidities, with added cardio-renal benefits. Dual agonists combining GLP-1 with other enteropancreatic hormones such as glucose-dependent insulinotropic polypeptide (GIP) have also been developed in recent years, leading to greater weight loss than using GLP-1 RAs alone. However, up to 40% of the weight lost with GLP-1 RAs comes from lean body mass, raising concerns about potential adverse effects on skeletal muscle function. Mitochondrial dysfunction, characterized by reduced mitochondrial size and activity, is prevalent in individuals with obesity and T2DM and is a known contributor to muscle wasting in ageing and some chronic diseases. This systematic review investigates the impact of GLP-1-based therapies on skeletal muscle mitochondrial function in individuals with obesity and T2DM or in related animal and cell models. A comprehensive search of MEDLINE, Scopus, CINAHL and clinicaltrials.gov was conducted. Inclusion criteria included randomized controlled trials, randomized crossover trials, cluster randomized control trials and basic science studies involving any GLP-1 RA or GLP-1/GIP dual agonist. Outcomes of interest were skeletal muscle respiratory function either in the form of measurements of mass, number, content, oxidative capacity/respiratory function, mitochondrial dynamics, mitochondrial biogenesis and mitophagy. Eight studies were eligible for analysis; no human studies were identified. All of the included studies used GLP-1 RAs (single agonists) as intervention. The emerging evidence suggests that GLP-1 RAs increase mitochondrial area, number and morphology (i.e., reduces swelling). Data are conflicting on the effect of GLP-1 RAs upon mitochondrial mass, respiration and the expression of uncoupling proteins and PGC-1α. Data also demonstrate muscle specific (i.e., soleus vs. extensor digitorum longus) responses to GLP-1 RAs. GLP-1 RAs appear to have a positive effect upon mitochondria area, number and morphology, but effects upon other aspects of mitochondrial health remain inconclusive. Data are very limited and solely presented in animal and invitro models. Future studies should be conducted in human populations in order to begin to understand the effect of GLP-1 RAs and GLP-1-based therapies on human skeletal muscle mitochondria.

Changes in body composition accompanied by glucagon-like peptide 1 receptor agonist (GLP-1RA) induced weight loss have drawn much attention. However, fewer studies have reported body composition changes in patients receiving dulaglutide therapy in Chinese population. A total of 70 overweight/obese type 2 diabetes mellitus (T2DM) patients who received dulaglutide therapy were included. Clinical data were collected. Visceral fat area (VFA) and body composition were also measured. Changes in clinical indicators and body composition of patients before and after intervention were also analyzed. Correlation analysis and multiple linear regression model were used to evaluate the association between hemoglobin A1C (HbA1c) and body composition. The results showed that body weight (BW), VFA, body fat (BF), lean body mass (LBM), skeletal muscle mass (SMM) and water content were reduced after 3 months dulaglutide intervention. The lean body mass percentage (LBMP) and skeletal muscle mass percentage (SMMP) significantly increased. Moreover, there was no significant difference in bone mineral quality (BMQ) after the intervention. The multiple linear regression model revealed that the % change in BF was independently associated with % change in HbA1c (β = 0.449, t = 3.148, p=0.002). These results indicate that dulaglutide intervention does not cause muscle and bone mass loss while inducing weight loss, and % change in BF was independently associated with improved glucose control during dulaglutide therapy. This study offers some positive results to support the clinical application of dulaglutide.

Drugs targeting the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) are emerging as treatments for type-2 diabetes and obesity. GIP acutely decreases serum markers of bone resorption and transiently increases bone formation markers in short-term clinical investigations. However, it is unknown whether GIP acts directly on bone cells to mediate these effects. Using a GIPR-specific antagonist, we aimed to assess whether GIP acts directly on primary human osteoclasts and osteoblasts. Osteoclasts were differentiated from human CD14+ monocytes and osteoblasts from human bone. GIPR expression was determined using RNA-seq in primary human osteoclasts and in situ hybridization in human femoral bone. Osteoclastic resorptive activity was assessed using microscopy. GIPR signaling pathways in osteoclasts and osteoblasts were assessed using LANCE cAMP and AlphaLISA phosphorylation assays, intracellular calcium imaging and confocal microscopy. The bioenergetic profile of osteoclasts was evaluated using Seahorse XF-96. GIPR is robustly expressed in mature human osteoclasts. GIP inhibits osteoclastogenesis, delays bone resorption, and increases osteoclast apoptosis by acting upon multiple signaling pathways (Src, cAMP, Akt, p38, Akt, NFκB) to impair nuclear translocation of nuclear factor of activated T cells-1 (NFATc1) and nuclear factor-κB (NFκB). Osteoblasts also expressed GIPR, and GIP improved osteoblast survival. Decreased bone resorption and improved osteoblast survival were also observed after GIP treatment of osteoclast-osteoblast co-cultures. Antagonizing GIPR with GIP(3-30)NH2 abolished the effects of GIP on osteoclasts and osteoblasts. GIP inhibits bone resorption and improves survival of human osteoblasts, indicating that drugs targeting GIPR may impair bone resorption, whilst preserving bone formation.

Obesity remains a major global health challenge, severely affecting metabolic and cardiovascular health. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists mark a significant breakthrough in diabetes and obesity management, significantly aiding in weight loss and glycemic control. Tirzepatide, a dual agonist for GLP-1 and GIP receptors, effectively promotes weight loss and improves metabolic parameters by influencing insulin secretion, appetite regulation, and gastric emptying. This review highlights the dual metabolic and psychological impacts of GLP-1 and GIP agonists in diabetes and obesity management, emphasizing the need for a holistic, patient-centered approach to optimize treatment outcomes. While GLP-1 and GIP agonists demonstrate significant metabolic benefits, their long-term use is often limited by gastrointestinal side effects and psychological impacts. These medications, while regulating appetite and food reward pathways, can also lead to mood disturbances and altered eating behaviors, potentially affecting patient adherence. A comprehensive strategy for obesity management using GLP-1 and GIP agonists must consider both metabolic and psychological factors. Future research should focus on elucidating the complex mechanisms underlying their psychological effects and integrating mental health considerations into therapeutic strategies. Personalized diet and exercise interventions, alongside pharmacological treatments, are crucial for enhancing both metabolic and psychological outcomes, ensuring a more sustainable and effective approach to managing obesity.

Aerobic Training (AT) and Resistance Training (RT) are the two common exercise modalities for weight managing and physical health. AT comprises rhythmic, continuous movement that improves cardiovascular endurance and calorie expenditure, whereas RT focuses on muscle strengthening through measured exercises with weights. There is a need for clear comparison research to guide tailored exercise programs for optimal health results. The research aims to compare the influences of RT and AT on weight reduction and body composition in adult individuals. The research proposed the Adaptive Decision Tree (ADT) to identify patterns in participant response and predict fat loss trends. A total of 40 adults aged 20–40 years, with fluctuating fitness backgrounds, were randomly allocated into two equal groups: one engaged in structured AT, and the other in RT-based routines. The intervention was ten weeks long. Participants charted a supervised protocol scheduled at 5 days/week for 30 min at a moderate intensity of AT exercise for the AT group and a full-body RT (3 days/week) routine with progressive overload targeting major muscle groups for the RT group. Pre- and post-intervention data were composed on lean mass, waist-to-hip ratio, body weight, and body fat percentage. Paired and independent t-tests, descriptive statistics, and Pearson correlation coefficient (PCC) were employed to assess within- and between-group differences. The statistical analysis was executed using SPSS v26, with a significance threshold of p &lt; 0.05. Results demonstrated that both groups presented decreased body fat mass and body weight, with the AT group indicating a superior average weight loss (−4.3 ± 1.2 kg) and the RT group showing a greater gain in lean body mass (+1.9 ± 0.8 kg). The ADT model achieved a higher R-squared value of 0.962084, lower RMSE and MAE, indicating strong predictive accuracy for fat loss trends. Overall, the research demonstrated that AT encourages better weight loss than RT training, but RT training affects positive changes in body composition. The shared insights support tailored program design based on individual health goals.

Type 2 diabetes mellitus (T2DM) was characterized by hyperglycemia and frequently accompanied by obesity and elevated cardiovascular risk. Incretin hormone-based therapies, especially glucagon-like peptide-1 receptor agonists (GLP-1 RAs), had demonstrated efficacy in glycemic control, weight reduction, and cardiovascular risk mitigation. Recently, dual agonists targeting both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors had emerged as promising therapeutic agents aiming to enhance these benefits. This review assessed the efficacy and safety of dual GLP-1/GIP agonists specifically regarding weight reduction and cardiovascular outcomes in patients with T2DM. A systematic literature search was conducted, prioritizing randomized controlled trials, meta-analyses, and high-quality observational studies published within the last decade on dual GLP-1/GIP agonists in T2DM management. Dual GLP-1/GIP receptor agonists produced superior weight loss and glycemic control compared to GLP-1 monoagonists, attributable to complementary incretin receptor signaling that enhances insulin secretion, suppresses glucagon, and reduces appetite. Cardiovascular outcome trials demonstrated noninferiority to established GLP-1 RAs and suggest potential additional cardioprotective effects, although evidence for superiority remains inconclusive. These dual agonists also exerted beneficial effects on risk factors such as lipid profiles and blood pressure. However, data heterogeneity and evolving trial designs merit cautious interpretation. Dual GLP-1/GIP agonists represented a significant advance in T2DM treatment, offering enhanced weight reduction and promising cardiovascular benefits. Further large-scale and long-term studies are warranted to fully characterize their cardiovascular protective profile and optimize clinical application. Keywords: Type 2 diabetes, Dual GLP-1/GIP agonists, Weight reduction, Cardiovascular outcomes, Incretins

What is already known about this subject Adolescence is an important period of physiological growth. Loss of central adiposity with preservation of lean mass during weight loss is optimal. There are discrepancies in the literature concerning changes in lean mass during weight loss in adolescents. What this study adds This study provides information of regional and total body composition change in adolescents during weight loss. This study controls for important factors that impact body composition in growing adolescents such as age, sex, height, baseline weight and race. This study provides correlations of changes in waist circumference and body mass index (BMI) with total and trunk fat mass during weight loss in adolescents. Background Changes in body composition during weight loss among obese adolescents are poorly understood. This study characterized the composition of weight loss and its association with changes in waist circumference (WC) in obese adolescents. Methods Total (Tot), trunk (Tr) and appendicular (Ap) fat mass (FM) and lean mass (LM) were measured by dual-energy X-ray absorptiometry in 61 obese adolescents (40 girls) who participated in a randomized controlled weight loss trial. Changes in body composition were assessed at 0, 6 and 12 months using mixed-effects regression models. Correlation analysis of change in WC and total and regional compartments of FM and LM were assessed. Results Weight loss for adolescents was 90.3% FM and 15.9% LM at 0-6 months, and 98.2% FM and 7% LM at 0-12 months. At 12 months, girls lost 2.67 kg more TotFM than boys in models adjusted for height, age, race and baseline weight. Boys gained LM in all compartments in all models. At 12 months, girls lost TotLM (2.23 ± 0.74, P < 0.004) and ApLM (0.69 ± 0.31, P = 0.03) and gained TrLM (0.37 ± 0.35, P = 0.29). The percentage LM, increased for boys and girls in all models. TotFM was correlated with body mass index (BMI) change with TotFM (R = 0.70-0.91, P = 0.001) and WC change (R = 0.53-0.55, P < 0.001). Conclusions Weight loss in obese adolescents during a weight loss trial using lifestyle management and sibutramine was primarily from trunk FM. Although absolute LM increased in boys and decreased in girls, the percentage of weight that is LM increased for both boys and girls. Changes in BMI were more reflective of changes in FM than changes in WC.

Resmetirom, an oral selective thyroid hormone receptor beta agonist, is the first pharmacological agent approved by the Food and Drug Administration (FDA) of the United States in 2024 for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with liver fibrosis stages F2 and F3. In the ongoing, registrational phase 3 MAESTRO-NASH study, the administration of resmetirom for 52 weeks led to MASH resolution and significant improvement in fibrosis by at least one stage as compared to placebo [1]. However, there remains a dearth of information about combining resmetirom with medications that are recommended for treating comorbidities of metabolic dysfunction-associated steatotic liver disease (MASLD), such as glucagon-like peptide 1 receptor agonists (GLP1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes (T2D) with and without obesity [2, 3]. Notably, around half of T2D patients have MASH [4]. Therefore, the prespecified analysis of MAESTRONASH by Noureddin et al. has provided timely evidence that in T2D patients, the efficacy of resmetirom on MASH end points was not affected by the stable background use of GLP1RA or SGLT2i [5], which are now commonly prescribed due to their established independent cardiovascular and kidney benefits. Both GLP1RA and SGLT2i have been shown to resolve and improve MASH in the recent Effect of Semaglutide in Subjects with Non-cirrhotic non-alcoholic steatohepatitis (ESSENCE) and Dapagliflozin Efficacy and Action in Non-alcoholic steatohepatitis (DEAN) trials, respectively, but residual risk remains [6, 7]. Indeed, in around 40% of the T2D participants from the MAESTRONASH trial, at baseline, their MASH remained present despite the use of either GLP1RA or SGLT2i for a reasonable period (median duration 660 days for GLP1RA and 651 days for SGLT2i) [5]. Although the GLP1RA used were mostly liraglutide, dulaglutide and semaglutide 1 mg weekly instead of semaglutide 2.4 mg weekly as in the ESSENCE trial, it reinforces the need to combine pharmacotherapies to target the different pathophysiological pathways in MASH [8]. The authors also demonstrated that resmetirom-treated participants who had weight loss ≥ 5%, as compared to those without, showed higher rates of MASH resolution and fibrosis improvement [5]. Further studies should be conducted to investigate if the sequence of initiating these MASH pharmacotherapies matters, for instance, whether starting GLP1RA after resmetirom can enhance its effect through inducing weight loss. Moreover, as several new incretin co-agonists such as tirzepatide, a GLP1- and glucose-dependent insulinotropic polypeptide (GIP) receptors co-agonist, as well as survodutide, a GLP1- and glucagon receptors co-agonist, with more potent weight-reducing effects, have also been shown to improve MASH in phase 2 trials [9, 10], their efficacy in combination with resmetirom also deserves further investigation. Compared with GLP1RA and SGLT2i, resmetirom is clearly a newcomer and is currently only available in the United States. It is anticipated that a lot of T2D patients with MASLD will already be on background SGLT2i and/or GLP1-based therapy when resmetirom becomes widely available. Therefore, the finding from this post hoc analysis that the combinations of these agents with resmetirom are safe and efficacious, is a clinically important outcome and a key step towards mastering MASH-targeted therapy in diabetes. Johnny Yau-Cheung Chang: conceptualization, writing – original draft. Chi-Ho Lee: conceptualization, writing – review and editing, supervision. C.-H.L. received advisory board and lecture honorarium from AstraZeneca, Ausmed, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, GSK, Novo Nordisk and Sanofi Aventis. The remaining author has no conflicts of interest. This article is linked to Noureddin et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70382. Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Cardiovascular biology of the GIP receptor

To test the hypothesis that an 8-year intensive lifestyle intervention (ILI) suppresses aging-dependent changes in regional lean mass (LM) and fat mass (FM) among people with overweight/obesity and type 2 diabetes. Regional body composition was measured by dual-energy X-ray absorptiometry within a subset of 1,019 volunteers (45-75 years old) in the Look AHEAD study randomized to ILI or diabetes support and education (DSE). The ILI goal was to achieve and maintain ≥7% weight loss through increased physical activity and reduced caloric intake. Over 8 years, the DSE group exhibited a linear loss of LM and FM. During year 1, the ILI group lost LM and FM. Between years 1 and 8, the ILI group regained most FM in all regions; regional LM converged with that of the DSE group; the percent of LM loss was greater for the leg than for the trunk. Among both groups, regional LM and FM change was proportional to the size of the region, trunk > leg > arm. Aging-dependent LM losses, particularly in the leg region, were not suppressed by ILI. The long-term consequences of rapid LM and FM loss and subsequent regain mostly as fat are unknown.

Background: We evaluated the effects of high-protein dairy milk ingestion on changes in body composition, strength, power, and skeletal muscle regulatory markers following 6 weeks of resistance training in trained young males. Methods: Thirty resistance-trained young males (age: 27 ± 3 years; training experience: 15 ± 2 months) were randomly assigned to one of two groups: high-protein dairy milk (both whey and casein) + resistance training (MR; n = 15) or isoenergetic carbohydrate (maltodextrin 9%) + resistance training (PR; n = 15). Milk and placebo were ingested immediately post-exercise (250 mL; 30 g protein) and 30 min before sleep (250 mL; 30 g protein). Before and after 6 weeks of linear periodized resistance training (4 times/week), body composition (bioelectrical impedance), strength, power, and serum levels of skeletal muscle regulatory markers (insulin-like growth factor 1 (IGF-1), growth hormone, testosterone, cortisol, follistatin, myostatin, and follistatin–myostatin ratio) were assessed. Results: The MR group experienced a significantly higher (p < 0.05) increase in lean mass, strength, and power (upper- and lower-body) than the PR group. Further, IGF-1, growth hormone, testosterone, follistatin, and follistatin–myostatin ratio were significantly increased, while cortisol and myostatin significantly decreased in the MR group than the PR group (p < 0.05). Conclusions: The strategic ingestion of high-protein dairy milk (post-exercise and pre-sleep) during 6 weeks of resistance training augmented lean mass, strength, power, and altered serum concentrations of skeletal muscle regulatory markers in trained young males compared to placebo.