The insulin resistance syndrome represents a metabolic state in which hyperinsulinemia and/or insulin resistance constitute the platform underlying the development of metabolic complications and related diseases such as diabetes and coronary heart disease. As described in this paper, these insulin-related changes are also involved in the regulation of energy balance and contribute to the recovery of body weight stability in a context of long-term positive energy balance. Under conditions of negative energy balance such as obesity treatment, this connection has a high clinical relevance. In this regard, relevant literature as well as the reanalysis of previously published data suggest that the beneficial effect of weight loss on insulin-related changes in glycemia cannot be disassociated from the relationship between changes in plasma insulin and those in resting energy expenditure. In clinical terms, this suggests that the beneficial effect of weight loss on components of the insulin resistance syndrome could be related to the development of a state of physiological vulnerability that complicates the control of body weight. This poses a major challenge to health professionals who then have to manage obesity treatment as the search for a compromise between the beneficial and potentially detrimental effects of weight loss on insulinemia and insulin sensitivity. This also reinforces the relevance to adhere to healthy diet and physical activity habits in order to maintain body weight stability rather than relying on the overuse of regulatory systems soliciting the effects of hyperinsulinemia on the control of energy intake and expenditure.