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Obesity and its metabolic consequences, such as insulin resistance and type 2 diabetes (T2D), have become a global health challenge. While peripheral regulation of glucose and lipid metabolism is well characterized, central brain regulation is also a key component in the control of energy and glucose homeostasis. However, knowledge remains limited regarding how these systems are integrated and how they affect or are affected by obesity and T2D. The overall aim of this thesis was to further elucidate the brain’s contribution to the development of obesity and T2D and to identify mechanisms that may be relevant for future interventions.

In Paper I, the short-term metabolic effects of obesity surgery (OS) and low-calorie diet (LCD) were compared in individuals with obesity using oral glucose tolerance testing, hyperinsulinaemic-euglycaemic clamp, and whole-body integrated 18F-FDG-PET/MRI. Although OS and LCD induced similar reductions in body weight and adiposity, only OS produced rapid improvements in fasting glucose homeostasis and insulin resistance, together with altered tissue-specific glucose uptake, indicating early metabolic effects beyond weight loss alone.

In Papers II–IV, the same rat cohort was used to examine the effects of cafeteria diet and caloric restriction over 12 weeks. In Paper II, the cafeteria diet induced a clear adverse metabolic phenotype with higher adiposity, insulin resistance, and prediabetes, whereas caloric restriction produced a somewhat healthier phenotype than controls. Despite these metabolic differences, behavioural profiling revealed no significant group differences. In Paper III, endocrine analyses showed that caloric restriction induced more pronounced hormonal alterations than the cafeteria diet, which caused only modest pituitary changes. Finally, in Paper IV, matrix-assisted laser desorption/ionization mass spectrometry imaging demonstrated widespread, region-specific changes in brain biogenic amine signalling after both dietary interventions, with overlapping neurochemical patterns despite opposite metabolic states.

In conclusion, this thesis demonstrates that obesity, caloric restriction, and metabolic interventions are associated with coordinated adaptations across peripheral metabolic regulation, endocrine regulation, and central neuro-chemical systems. Moreover, it shows an important role of brain-periphery crosstalk in metabolic disease, and highlights central pathways that may serve as potential targets for future clinical interventions, aiming to improve the prevention and treatment of obesity and T2D.