The hypothalamus controls feeding through homeostatic mechanisms. Obesity occurs when there is an imbalance between energy intake and energy expenditure, and the hypothalamus is at the centre of it. Under normal circumstances, long-term energy balance is centrally regulated by the hypothalamus receiving peripheral input.^{2, 10, 11} The imbalance in energy intake and expenditure can result from changes in these peripheral signals, as well as other factors such as genetic predisposition and the impact of medications.^{2, 10, 11}

The mesolimbic system is the key for non-homeostatic feeding i.e., feeding which does not occur to maintain homeostatic balance but for other reasons including learning, memory and cognitive processes.^{12, 13} Therefore, it affects feeding based upon hedonic adaptation and past learnt experiences.¹³ This mesolimbic area can override both physiological hunger and satiety to influence feeding behaviour.¹³ In particular, palatable food increases dopamine levels in the mesolimbic system.¹³ Highly palatable food may contain the same number of calories as less palatable food but is more processed with fewer nutritive elements such as fibre and higher levels of sugar and/or salt and/or fat per portion.¹⁴ Dopamine is also linked to conditional cues (previous learned experiences) associated with food as a reward and opioid signalling in the mesolimbic area also contributes to this.¹³ These mechanisms allow food consumption (particularly of palatable foods) to be used as an incentivising reward despite satiety signals.¹³

The prefrontal cortex is involved in higher cognitive and executive control functions such as regulating emotions, impulses, desires and cravings including those in relation to food.¹⁵ This region can typically counteract the mesolimbic system in its emotional and reward-cue based feeding. However, in stressful situations the prefrontal cortex is dampened down in favour of the mesolimbic system, and this increases automatic survival mechanisms such as food hypervigilance.¹⁵ Both acute and chronic stressors increase synamptic branching in the amygdala whilst reducing the synaptic contacts with the prefrontal region.¹⁵ In this way, during a chronic stress, a network develops in the brain which favours mesolimbic responses.¹⁵ This results in a strong drive to eat which combined with an impaired capacity to inhibit eating can lead to obesity.¹⁵

Leptin is produced by adipose tissue and acts in the hypothalamus to prevent weight gain by reducing food intake and decreasing the motivational drive for palatable foods.^19,20 However, although there are higher levels of circulating leptin in people living with obesity, this does not suppress food intake.³ Food restriction i.e. dieting is a common method used to try and prevent overweight.²¹ However, the lost weight is often followed by compensatory growth when the restriction ends which can result in overweight.²¹ A key factor in whether overweight develops may be effectiveness of leptin signal.²¹

Insulin levels correlate with energy balance and levels fall with starvation and rise with obesity.³ Insulin is a key hormone involved in glucose homeostasis through actions on skeletal muscle, liver and adipose tissue.²² In the brain, insulin suppresses neuropeptide Y which promotes weight gain through increased feeding and decreased energy expenditure.³ Therefore, insulin can counteract weight gain.³ When higher circulating insulin levels are necessary to achieve glucose homeostasis, a subject is considered insulin resistant.²² Extensive studies on the molecular aetiology of type 2 diabetes have revealed that low-grade chronic inflammation in those living with obesity mediates insulin resistance which can lead to type 2 diabetes.²³

Menopausal women are three times more likely to develop obesity compared to premenopausal women.¹⁶ Decreased levels of oestrogen play an important role in the development of obesity in menopausal women.¹⁶ The absence of oestrogen causes a variation in the lipid profile of post-menopausal and also causes predominant abdominal fat accumulation.¹⁶ Indeed, a meta-analysis of over 100 randomised trials in menopausal women has analysed the effect of hormone replacement therapy (HRT) containing oestrogen on components of metabolic syndrome found HRT containing oestrogen increased lean body mass, reduced abdominal fat and improved insulin resistance.¹⁶

Growth hormone stimulates growth in children and in adults. Its main role is to regulate metabolism.²⁴ Growth hormone secretion, both spontaneous and that evoked by stimuli, is blunted in obesity.¹⁷ The pathophysiologic role of growth hormone in obesity is yet to be fully understood, however administering growth hormone has been linked to weight loss and metabolic efficacy of lean body mass in those living with obesity.¹⁷

Similarly, thyroid hormones are consistently dysregulated in obesity. Sub-clinical hypothyroidism with elevated TSH and normal peripheral thyroid hormone concentration has been consistently found in obese subjects.¹⁸