Why certain hormones affect body weight

Obesity is not always the result of over eating; it is often the result of a biological hormone disorder. In this article, Claudia Louch of the Harley Street Nutrition Clinic explains the role of leptin in abnormal weight gain.

Obesity and biological disorders

Before the discovery of the adipocyte hormone leptin, obesity was thought to result more from a lack of will power than from an underlying biological disorder. Now, 15 years after leptin's discovery, a much different picture of how obesity occurs is beginning to emerge. At its heart is evidence that consuming a high-fat diet induces inflammation in key neuronal systems that govern energy homeostasis, an effect that increases the defended level of body weight.

What causes insulin resistance and leptin blocking?

The discovery of the link between feeding, hypothalamic inflammation, and the control of body weight is rooted in the study of insulin resistance. This develops when tissues are exposed to a supply of nutrients that exceeds their energy requirements. In muscle, liver, fat tissue, and the vasculature, sustained exposure to excess nutrient intake induces cell inflammation via multiple mechanisms. In addition, the recruitment and activation of immune cells in fat tissue of obese individuals, nutrient excess can also induce inflammation via cell-autonomous mechanisms. For example, exposure of many cell types (e.g., fat cells, macrophages, and endothelial cells) to saturated fatty acids such as palmitate (palm fat) activates the proinflammatory pathway. Nutrient excess can also trigger cell inflammation by raising intracellular levels of free radicals, causing cell damage. This inflammatory response, in turn, causes insulin resistance. Importantly, these inflammation-induced responses block signalling by leptin as well as by insulin.

Why leptin and insulin can cause obesity

Given the diversity of tissues affected by nutrient excess, it is perhaps unsurprising that the hypothalamus is also susceptible. Unlike inflammation in peripheral tissues, however, this hypothalamic response has the potential to cause obesity, rather than simply being its consequence. This is because leptin and insulin are crucial signals that convey “fat cell negative feedback” information to the hypothalamus regarding the amount of body fuel stored as fat. When input from these hormones is reduced, therefore, the hypothalamus perceives this as evidence of reduced body fat and triggers an adaptive increase of food intake relative to energy expenditure that favours weight gain.

Why weight lost through calorie-restricted diets is hard to keep off

Indeed, the same phenomenon helps to explain why it is so hard to keep off weight lost through calorie-restricted diets. Accordingly, when inflammation-induced impairment of insulin and leptin occurs, this causes a state of positive energy balance until body fat stores, along with plasma leptin and insulin concentrations, rise sufficiently to overcome the resistance. This picture - increased plasma insulin and leptin levels, combined with the defence of an elevated level of body weight - is characteristic of common obesity.

Understanding leptin resistance

The concept that common forms of obesity might arise from hypothalamic leptin resistance is not new, having first been reported in rodent models of diet-induced obesity nearly a decade ago. But broad acceptance of acquired leptin resistance as a cause of common obesity has been hampered both by a lack of insight into how it occurs and by uncertainty about whether it is simply a consequence of obesity and not a cause. By offering an answer to the first question, the emerging role of hypothalamic inflammation is beginning to clarify the second.

Events triggered by a high-fat diet

The deleterious cascade of events initiated by a high-fat diet are: hypothalamic inflammation, leptin resistance, obesity, and peripheral metabolic dysfunction.

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Why certain hormones affect body weight
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