Weight loss is an important goal in the management of several chronic conditions, including type 2 diabetes mellitus, and pharmacological therapies that aid weight loss are appealing. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) are novel glucose-lowering therapies that have been shown to induce clinically significant reductions in body weight. However, this weight loss may not be attributed solely to fat mass (FM). Given the importance of skeletal muscle and lean body mass (LBM) on cardio-metabolic health and physical function, we reviewed the available literature reporting the effects of GLP-1RAs and SGLT2is on body composition. Results demonstrate that, in most circumstances, the weight loss associated with both therapies predominantly comprises a reduction in FM, although significant heterogeneity exists between studies. In over half of the studies identified, the proportion of LBM reduction ranged between 20% and 50% of total weight lost, which is consistent with diet-induced weight loss and bariatric surgery. No clear differences existed between GLP-1RAs and SGLT2is. Consequently, the loss of LBM and skeletal muscle associated with weight loss induced by GLP-1RAs and SGLT2is warrants attention. Strategies to preserve skeletal muscle and improve physical function, for example through structured exercise, are of great importance.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs, incretin mimetics) and dipeptidyl peptidase-4 inhibitors (DPP-4is, incretin enhancers) are glucose-lowering therapies with proven cardiovascular safety, but their effect on microvascular disease is not fully understood. Both therapies increase GLP-1 receptor agonism, which is associated with attenuation of numerous pathological processes that may lead to microvascular benefits, including decreased reactive oxygen species (ROS) production, decreased inflammation and improved vascular function. DPP-4is also increase stromal cell-derived factor-1 (SDF-1), which is associated with neovascularisation and tissue repair. Rodent studies demonstrate several benefits of these agents in the prevention or reversal of nephropathy, retinopathy and neuropathy, but evidence from human populations is less clear. For nephropathy risk in human clinical trials, meta-analyses demonstrate that GLP-1RAs reduce the risk of a composite renal outcome (doubling of serum creatinine, eGFR reduction of 30%, end-stage renal disease or renal death), whereas the benefits of DPP-4is appear to be limited to reductions in the risk of albuminuria. The relationship between GLP-1RAs and retinopathy is less clear. Many large trials and meta-analyses show no effect, but an observed increase in the risk of retinopathy complications with semaglutide therapy (a GLP-1RA) in the SUSTAIN-6 trial warrants caution, particularly in individuals with baseline retinopathy. Similarly, DPP-4is are associated with increased retinopathy risk in both trials and meta-analysis. The association between GLP-1RAs and peripheral neuropathy is unclear due to little trial evidence. For DPP-4is, one trial and several observational studies show a reduced risk of peripheral neuropathy, with others reporting no effect. Evidence in other less-established microvascular outcomes, such as microvascular angina, cerebral small vessel disease, skeletal muscle microvascular disease and autonomic neuropathies (e.g. cardiac autonomic neuropathy, gastroparesis, erectile dysfunction), is sparse. In conclusion, GLP-1RAs are protective against nephropathy, whereas DPP-4is are protective against albuminuria and potentially peripheral neuropathy. Caution is advised with DPP-4is and semaglutide, particularly for patients with background retinopathy, due to increased risk of retinopathy. Well-designed trials powered for microvascular outcomes are needed to clarify associations of incretin therapies and microvascular diseases. Graphical Abstract

Acute exercise does not elicit compensatory changes in appetite parameters in lean individuals; however, less is known about responses in overweight individuals. This study compared the acute effects of moderate-intensity exercise on appetite, energy intake and appetite-regulatory hormones in lean and overweight/obese individuals. Forty-seven healthy lean (n=22, 11 females; mean (s.d.) 37.5 (15.2) years; 22.4 (1.5) kg m⁻²) and overweight/obese (n=25, 11 females; 45.0 (12.4) years, 29.2 (2.9) kg m⁻²) individuals completed two, 8 h trials (exercise and control). In the exercise trial, participants completed 60 min treadmill exercise (59 (4)% peak oxygen uptake) at 0–1 h and rested thereafter while participants rested throughout the control trial. Appetite ratings and concentrations of acylated ghrelin, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) were measured at predetermined intervals. Standardised meals were consumed at 1.5 and 4 h and an ad libitum buffet meal was provided at 7 h. Exercise suppressed appetite (95% confidence interval (CI) −3.1 to −0.5 mm, P=0.01), and elevated delta PYY (95% CI 10 to 17 pg ml⁻¹, P<0.001) and GLP-1 (95% CI 7 to 10 pmol l⁻¹, P<0.001) concentrations. Delta acylated ghrelin concentrations (95% CI −5 to 3 pg ml⁻¹, P=0.76) and ad libitum energy intake (95% CI −391 to 346 kJ, P=0.90) were similar between trials. Subjective and hormonal appetite parameters and ad libitum energy intake were similar between lean and overweight/obese individuals (P ⩾ 0.27). The exercise-induced elevation in delta GLP-1 was greater in overweight/obese individuals (trial-by-group interaction P=0.01), whereas lean individuals exhibited a greater exercise-induced increase in delta PYY (trial-by-group interaction P<0.001). Acute moderate-intensity exercise transiently suppressed appetite and increased PYY and GLP-1 in the hours after exercise without stimulating compensatory changes in appetite in lean or overweight/obese individuals. These findings underscore the ability of exercise to induce a short-term energy deficit without any compensatory effects on appetite regardless of weight status.

Summary: This systematic review and meta‐analysis determined the impact of structured exercise training, and the influence of associated weight loss, on intrahepatic triglyceride (IHTG) in individuals with non‐alcoholic fatty liver disease (NAFLD). It also examined its effect on hepatic insulin sensitivity in individuals with or at increased risk of NAFLD. Analyses were restricted to studies using magnetic resonance spectroscopy or liver biopsy for the measurement of IHTG and isotope‐labelled glucose tracer for assessment of hepatic insulin sensitivity. Pooling data from 17 studies (373 exercising participants), exercise training for one to 24 weeks (mode: 12 weeks) elicits an absolute reduction in IHTG of 3.31% (95% CI: −4.41 to −2.22%). Exercise reduces IHTG independent of significant weight change (−2.16 [−2.87 to −1.44]%), but benefits are substantially greater when weight loss occurs (−4.87 [−6.64 to −3.11]%). Furthermore, meta‐regression identified a positive association between percentage weight loss and absolute reduction in IHTG (β = 0.99 [0.62 to 1.36], P < 0.001). Pooling of six studies (94 participants) suggests that exercise training also improves basal hepatic insulin sensitivity (mean change in hepatic insulin sensitivity index: 0.13 [0.05 to 0.21] mg m⁻² min⁻¹ per μU mL⁻¹), but available evidence is limited, and the impact of exercise on insulin‐stimulated hepatic insulin sensitivity remains unclear.

Obesity is a primary antecedent to non-alcoholic fatty liver disease whose cardinal feature is excessive hepatic lipid accumulation. Although total hepatic lipid content closely associates with hepatic and systemic metabolic dysfunction, accumulating evidence suggests that the composition of hepatic lipids may be more discriminatory. This review summarises cross-sectional human studies using liver biopsy/lipidomics and proton magnetic resonance spectroscopy to characterise hepatic lipid composition in people with obesity and related metabolic disease. A comprehensive literature search identified 26 relevant studies published up to 31^st March 2021 which were included in the review. The available evidence provides a consistent picture showing that people with hepatic steatosis possess elevated saturated and/or monounsaturated hepatic lipids and a reduced proportion of polyunsaturated hepatic lipids. This altered hepatic lipid profile associates more directly with metabolic derangements, such as insulin resistance, and may be exacerbated in non-alcoholic steatohepatitis. Further evidence from lipidomic studies suggests that these deleterious changes may be related to defects in lipid desaturation and elongation, and an augmentation of the de novo lipogenic pathway. These observations are consistent with mechanistic studies implicating saturated fatty acids and associated bioactive lipid intermediates (ceramides, lysophosphatidylcholines and diacylglycerol) in the development of hepatic lipotoxicity and wider metabolic dysfunction, whilst monounsaturated fatty acids and polyunsaturated fatty acids may exhibit a protective role. Future studies are needed to prospectively determine the relevance of hepatic lipid composition for hepatic and non-hepatic morbidity and mortality; and to further evaluate the impact of therapeutic interventions such as pharmacotherapy and lifestyle interventions.

Hepatokines are liver-secreted proteins with potential to influence glucose regulation and other metabolic parameters. This study investigated differences in adiposity status on 5 novel hepatokines and characterised their response to acute moderate-intensity exercise in groups of normal-weight and overweight/obese men. Twenty-two men were recruited into normal-weight and overweight/obese groups (body mass index: 18.5 to 24.9 and 25.0 to 34.9 kg·m⁻²). Each completed 2 experimental trials, exercise and control. During exercise trials, participants performed 60 min of moderate-intensity treadmill exercise (∼60% peak oxygen uptake) and then rested for 6 h. Participants rested throughout control trials. Circulating fibroblast growth factor-21 (FGF21), follistatin, leukocyte cell-derived chemotaxin 2 (LECT2), fetuin-A, and selenoprotein-P (SeP) were measured throughout. Fasted (resting) FGF21 and LECT2 were higher in overweight/obese individuals (129% and 55%; P ≤ 0.01) and correlated with indices of adiposity and insulin resistance; whereas circulating follistatin was lower in overweight/obese individuals throughout trial days (17%, P < 0.05). In both groups, circulating concentrations of FGF21 and follistatin were transiently elevated after exercise for up to 6 h (P ≤ 0.02). Circulating fetuin-A and SeP were no different between groups (P ≥ 0.19) and, along with LECT2, were unaffected by exercise (P ≥ 0.06). These findings show that increased adiposity is associated with a modified hepatokine profile, which may represent a novel mechanism linking excess adiposity to metabolic health. Furthermore, acute perturbations in circulating FGF21 and follistatin after exercise may contribute to the health benefits of an active lifestyle.