**4. Integration of vitamin D in obesity treatment**

Obesity is caused by many factors, but despite the genetic contribution, it was observed to occur mainly due to lifestyle habits, which indicates that it can be

modified through some interventions or health awareness campaigns. The WHO has identified physical inactivity and unhealthy diet as one of the risk factors for noncommunicable diseases (NCDs), and it urges all efforts to contribute in reducing them to prevent deaths from NCDs [45].

Identifying and understanding the mechanism beyond low vitamin D status in obesity has a great importance in deciding the needed and required vitamin D replacement doses for obese individuals [40].

A study discussed the possibility of integrating vitamin D supplementation with current strategies, and it was suggested that the induction of adipocyte death through apoptosis is a very promising strategy to manage obesity [60–62].

When the adipocytes reach a maximum size, elevation in adipose tissue mass includes as well an elevation in adipocyte number. So, weight loss can result from not only a decrease in adipocyte size but also adipocyte number and can result in the loss of adipose tissue mass. The removal of adipocytes by a process called apoptosis decreases body fat and can contribute to the long-lasting control of weight loss [60–62]. The effects of the hormonal form of vitamin D, 1,25(OH)2D3, on apoptotic cell death are mediated through several signaling pathways on cellular calcium Ca2+ [60–62].

High calcium and vitamin D3 intake is linked to the stimulation of the calciumdependent apoptotic proteases in adipose tissue. The 1,25(OH)2D3-induced cellular calcium signal acts as an apoptotic initiator that directly recruits calciumdependent apoptotic effectors that are able of causing apoptosis in adipose tissue. It was observed that 1,25(OH)2D3 induces a prolonged elevation in intracellular calcium concentration (the apoptotic Ca2+ signal) and is also associated with low lipid accumulation in mature adipocytes [63].

Some studies revealed that vitamin D deficiency was closely associated with enhanced risk of major adverse cardiovascular diseases (CVD) [64, 65]. Some trials revealed a tendency toward a decrease in CVD risk with vitamin D supplementation as well, but the correlation was not significant [66]. Observational studies have indicated that high 25-hydroxyvitamin D [25(OH)D] levels were associated with a favorable serum lipid profile [67]. However, a solid rationale for such association is hard to identify unless there is an effect of vitamin D supplementation on serum lipids in placebo-controlled randomized trials. Unfortunately, the intervention studies gave different results ranging from positive to negative effect [67].

However, some randomized controlled trials (RCTs) studying the effect of supplementation on weight loss in overweight or obese people showed inconsistent results [68].
